Friday, 4 May 2018

#MSis1not2or3diseases: do you agree?

This post makes the case, yet again, for MS being one disease and that PPMS is no different to other types of MS. Do you agree?



I have had the busiest week clinically for some time with four MS clinics in fours days. I typically only do 1.25 clinics per week (one every Tuesday and one on the first Thursday of the month). Why so little? I am only employed by the NHS for 20% of my time with 80% earmarked for research, teaching, management and other academic activities (grant and paper writing, manuscript and grant reviews, clinical trials, work for charities, Brain Health and MS in the 21st Century initiatives, blogging and social media activities, consulting, etc.). 

The week was tough as I have had to deal with severe jet-lag from the AAN, but overall it was very enjoyable.

Several patients I saw had self-diagnosed themselves as having secondary progressive MS and asked me if I agreed with them. In comparison, several patients with more advanced MS, who were clearly getting worse, were in denial about the possibility of having entered the so-called progressive phase of the disease.

The issue I have is that since we published our therapeutic lag and asynchronous progressive MS hypotheses, under the length-dependent axonopathy theory of MS I am having increasing difficulty sticking to the old terminology that splits MS into two or three diseases. I think as a community the time is right to change the way the world thinks about the classification of MS. It is time to energise our campaign around #MSis1not2or3diseases. Do you agree?

People in the field of MS simply accept the dogma that PPMS in non-inflammatory form of MS and that PPMSers don't have relapses and that PPMS is a different disease to relapse-onset MS.

Studies looking at the pathology of progressive MS show without doubt that PPMS is inflammatory, albeit at a slightly lower level than SPMS. Because we view MS through the spectacles of an MRI scanner people think PPMS is non-inflammatory; PPMSers have fewer new or gadolinium-enhancing lesions. This is wrong, PPMSers have both. In addition, focal inflammation may be occurring at a level below the detection level of the MRI. What an MRI sees in relation to focal lesions is simply the tip of the iceberg. This is why we are increasingly using spinal fluid neurofilament levels to monitor disease activity.

Please note almost all PPMSers have oligoclonal IgG in their CSF. If there were no inflammation surely you would expect PPMS to be OCBs negative. In addition in almost all PPMS trials done to date a proportion, albeit a small proportion, go onto have relapses. In the Rituximab PPMS trial (Olympus), 11 out of 439 (2.5%) of study subjects had a relapse during the 96 weeks of the trial. In the more recent Ocrelizumab (ORATORIO) study protocol-defined relapses were reported for 11% of subjects in the placebo group and 5% subjects in the ocrelizumab group. Similarly, about 5% of study subjects in the glatiramer acetate PPMS (PROMISE) trial had relapses. Unfortunately, the exact number of relapses is not reported in the main manuscript. What is reported is MRI activity; 14% of 938 study subjects had Gd-enhancing lesions on MRI during the study. The latter is the MRI equivalent of relapses.

In summary, PPMSers have relapses. Based on this data how can we say that PPMS is non-relapsing?

Some people still claim that PPMS is a different disease to SPMS. It not uncommon in siblings pairs with MS for one to have relapse-onset MS and the other to have PPMS. The figure from a UK sibling study is ~25%. This fact alone indicates to me that relapse onset and PPMS are the same disease. Other arguments in favour of PPMS and SPMS being the same disease relates to genetic and natural history studies. PPMSers and relapse-onset MSers have the same genetic background. Once people with relapse-onset MS enter the so-called clinical phase of SPMS they progress at exactly the same rate as PPMSers.

It is for these reasons that I am convinced MS is one disease and that there is a strong case for doing trials on combined populations of so-called advanced MS. In other words, we should combine PPMS and SPMS populations into one study. I am aware that this is a controversial topic, particularly in the eyes of the regulators, but it needs serious consideration. If we don't do this then treatments will continue to be licensed for one subtype of progressive MS, and not the other clinical subtype, until additional trials are done. This is not in the interests of pwMS. Additional trials cost money and time. Time is not a something that progressive MSers have on their side. Five years in the life of someone with advanced MS may be the difference between using a walking-stick and becoming bed-bound.

Another issue is the concept that still pervades the field is that once you have progressive MS it is untreatable. One patient said to me: 'but, SPMS is an untreatable disease’. These attitudes entrench the concept of the therapeutic window in MS and perpetuate the concept that it is futile to treat SPMS. I disagree with both of these positions and prepared to go out on a limb and state that the therapeutic window remains open throughout the course of MS and it is not futile to try an develop treatments for SPMS. We have to give people with MS hope. Both the ASCEND (natalizumab) and EXPAND (siponimod) Trials were clearly positive in SPMS. Although the natalizumab (ASCEND) study did not hit the desired primary outcome natalizumab did show a strong treatment effect on hand and arm function. Surely a treatment that protects upper limb function in people with SPMS is worth the effort? These observations underpin our #ThinkHand campaign and why we want to do our #ChariotMS study. To quote one of my patients with SPMS: 'Now that I am in a wheelchair my hands and arms have become my legs’.

Do I also need to remind you that the ORATORIO trial of ocrelizumab in PPMS was also positive? Is ocrelizumab really superior to natalizumab? I would argue no. The differences between the ASCEND and ORATORIO trials can be explained on differences in the study populations. The ASCEND SPMS population was older and more disabled; over 60% of study subjects had an EDSS of 6.0 or 6.5. In other words, they had lost most meaningful reserve capacity in the motor system to their legs.

We know from other studies done on subjects with a disability level of EDSS of 6.0 (unilateral support) or 6.5 (bilateral support) that the EDSS is not a very good outcome measure over 2 years. Most MSers with this level of disability spend many years at these levels before progressing to a higher level of disability. In measurement speak, we refer to this as the ceiling effect of the EDSS. In comparison over 60% of PPMSers in the ORATORIO study had an EDSS of less than 6.0 and hence were at a level of disability on the EDSS scale that is more likely to move. In addition, with a disability below EDSS 6.0 there is more reserve capacity in the motor system to allow recovery of function and get a read-out in a two year period. In other words at lower levels of disability, there is less therapeutic lag.

For the last 4-5 years, I have been discussing two concepts, or hypotheses, on this blog, i.e. therapeutic lag and the length-dependency. The results of these two studies, with other evidence - new and old - strongly support both these related hypotheses. Therapeutic lag states that the more reserve that is lost in a specific pathway the longer it will take to see a treatment effect in relation to therapies that are targeting MS specific mechanisms. This is why the ORATORIO trial was positive on both the EDSS and timed-25-foot walk (T25FW), and the ASCEND trial was negative on both these outcome measures. I predicted correctly that if the ASCEND trial had been longer in duration then it would have been positive on both of these outcomes, in particular, the T25FW which is more sensitive to change than the EDSS. Unfortunately, the ASCEND trial did not allow for therapeutic lag, which is why I keep badgering Biogen to do an ASCEND-plus trial; i.e. to redo the ASCEND trial and include MSers in wheelchairs and to design the study with the 9-HPT being the primary outcome measure. This is what we are doing with ocrelizumab in PPMS; Roche will hopefully be in a position to announce the ORATORIO-plus trial based on these exact principles. I am convinced these hypotheses are correct as the treatment effect of ocrelizumab was greater on upper limb function, as assessed using the 9-hole peg test, than on lower limb function (EDSS & T25FW) in the ORATORIO PPMS study.

So what have we learnt?

  1. That non-relapsing progressive MS is a tractable problem; if we focus on the relevant outcomes, i.e. neuronal systems that have sufficient reserve capacity to demonstrate a treatment effect using responsive outcome measures such as the 9HPT and the ABILHAND we have a chance of a positive trial.
  2. If we are going to continue to have to use the EDSS as an outcome measure we are either going to have to study an earlier population, similar to the ORATORIO study population, or do longer studies to allow for therapeutic lag.
  3. We need to ditch the EDSS as a primary outcome measure in progressive MS trials. For those of us old enough to remember we have seen evidence for these arguments in relation to the interferon in SPMS trials. The European interferon-beta-1b SPMS trial was positive when the North American study was negative; the former was in a younger less disabled population, whereas the latter was older and more disabled population.
  4. If we are going to do studies in more advanced MS then we need to focus our attention on neuronal systems with functional reserve, for example, upper limb and bulbar function (speech and swallowing). For this to occur we will need to bring the regulators (EMA and FDA) on board. I think this has become a reality (watch this space).
  5. I suspect that to have a realistic chance to modify the non-relapsing progressive phase of MS we will need to use highly-effective DMTs. I am not surprised that ocrelizumab, natalizumab and siponimod have produced positive trial results in these populations; please note my emphasis on positive. Because of this, we have been lobbying Pharma to do trials in advanced progressive MS (both PPMS and SPMS combined) with the highly effective DMTs, i.e. natalizumab, alemtuzumab, ocrelizumab, ofatumumab, cladribine and ozanimod. The good news is that alemtuzumab is going into PPMS (sadly only up to EDSS 6.5), ocrelizumab back into PPMS (up to EDSS 8.0) and possibly cladribine (up to EDSS 8.0, #ChariotMS). We wait to hear about whether or not ofatumumab, ozanimod and natalizumab will be going into progressive MS and what cutoffs of EDSS will be used. 
The cynic in me worries more about the payers than the regulators. The cost-effectiveness calculations in relation to DMTs are based on the cost of the treatment versus the savings to the individual and society. Once a person with MS has lost their mobility they have already accrued a large amount of personal and societal costs. These include both direct medical cost and indirect costs for example loss of employment. The sad thing once a person becomes unemployed their worth to society drops. If this is the case then the payers, for example, NICE, may judge the cost-effectiveness of DMTs in more advanced MS to be less favourable; in other words expensive high-cost drugs such as natalizumab and ocrelizumab may not be cost-effective in more advanced MS compared to say early MS when preservation of physical functioning and employment will save society more money.

This is one reason why Pharma are reluctant to take on the risk and develop drugs for more advanced progressive MS, i.e. for MSers in wheelchairs. A potential way to counter this is to allow Pharma and payers to agree to a differential payment scale; the more disabled a person with MS is the less the company is able to charge for their drug. This may sound counterintuitive but it makes a lot of sense; it would force pharma to move to an outcomes-based remuneration system. Under this system, payers will get better value for money and pwMS will get treatments that work. This will allow us to move away from a fixed-pricing system to a value-based pricing system. We seem to be getting used this in many other sectors, surge pricing systems are used by the airlines, software industry and Uber.

I can see a world where the same DMT is more expensive when used in early MS and as the patient becomes more disabled the price of the drug drops. The question is the NHS and the Pharmaceutical sector ready for valued-based pricing? I think so this is already being explored in oncology. Why should the NHS, or individual, pay for something that doesn’t work? On the other hand, why should we deny people with progressive MS drug X because it is considered not cost-effective at their stage of the disease?


ProfG    

43 comments:

  1. This post is for Professor Chris Hawkes to read.

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    1. Who is Chris Hawkes and why specifically for him?

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    2. Editor of Multiple Sclerosis and related Disorders

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  2. Great post I am sure you are right. Why don't you have a debate at ECTRIMS on this topic? It is clear that it is very important for people such as me living with MS and on the cusp of needing a wheelchair.

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  3. Prof G,

    In reality this means nothing for someone with MS (whatever stage they are at). If I came to your clinic next week and was diagnosed with PPMS (I'm a 58 year old male), there is nothing you can prescribe me. PPMS is untreatable whatever you say. If the experts in this field were so great we wouldn't have young adults in wheelchair or others heading off to Switzerland. You and your colleagues treat PPMS the same as 20 years ago - pat patient on the head, say there's nothing you can do, send them on their way. No neuroprotectants, no remyelination treatments, no neurorestoratives therapies. I can't see this changing before you retire. I pray to my God that you never get PPMS as you couldn't cope with the reality - the neuro offers you nothing!

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    1. You miss the point; you don't have PPMS you have MS. If you were in our centre we would screen you to see if you had active disease (focal MRI activity and/or raised CSF-NFL levels) and we would offer you a DMT. As for neuroprotection, remyelination, etc. there are no licensed treatments only potential trials.

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    2. "..we would offer you a DMT."

      I bet most of people with worse MS nowadays have already had enough of them DMTs. Despite this, they accumulated disability while experiencing all the side effects. Offering some more DMTs is really the best thing you can do?

      Ever thought that less inflammation and less relapses for EDSS>6 might be the result of less mobility?

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    3. If the highly effective DMTs are doing their jobs, you'll already be noticing far fewer people in their 40s at your clinics with SPMS type disease?

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  4. I wondered about Marburg acute MS and if this is a form of PPMS, or if this is a different disease essentially?
    but having read about it is been found responsive to Alemtuzumab and Mitoxantrone.

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  5. You talk about cost of the drug and the reluctance of Pharma to test and NICE to authorise them for people with advanced MS. Why then the reluctance to place more emphasis or promotion of the use of off-label cladribine. Its cheap as chips but is it that different from Movenclad? Are there other off-label drugs that fall into the same category?

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    1. Yes several. Please see our essential off-label list. The question is we don't have data on whether any of them really work in wheelchair users, which is why we need to do trials.

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  6. Why some patients get a first diagnosis of SPMS even if they never had relapses and not a PPMS one? I have seen a couple of such cases. How can a doctor distinguish the two? Lesions?

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    1. No. The diagnosis of SPMS is based on a preceding history of at least one relapse.

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  7. The blogs' reaction "scale" (i.e. Good, Very Good, Excellent) doesn't go far enough - this article needs a further descriptor as its content exceeds excellent. Perhaps "Most bodacious" as Bill and Ted would have said in the late 1980's, perhaps? "Beyond excellent" is probably a reasonable modern equivalent.

    So, if inflammation is key (which I'm sure it is), why do some people with PPMS lack oligoclonal bands? Maybe this subset of pwMS (which includes myself) have a different condition or a specific kind of MS? Thoughts from Prof G and the team would be appreciated.

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    1. Even if oligoclonal bands are absent, which I suspect in some cases might be due to a possible lack of sensitivity in detection methods, there might still be immunoglobulin present in the brain itself rather than the CSF. Also absence of OCB does not preclude ongoing inflammation in PPMS, with the involvement of other cell types such as microglia and astrocytes. Just submitted a paper on this very subject.

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    2. Yes, there is the issue of test sensitivity with some OCB negative PPMS being positive when analysing kappa and lambda light chains. However, OCB-ve PPMS behaves differently to OCB+ve PPMS (worse prognosis).

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  8. Different types/presentations of MS may not be different diseases, but in my opinion they require different treatments and I do not believe that immunosuppression would be the way to go for my progressive MS. I believe such drugs would just present another set of problems. In my opinion, what is required for effective treatment of progressive MS with an acceptable risk/benefit profile are neuroprotectives, repair agents. Until such drugs are developed, there's not a lot to shout about.

    "The sad thing once a person becomes unemployed their worth to society drops."

    Obnoxious. And not necessarily true.

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    1. The lack of any available neuroprotectant for MS is a source of much frustration to me, particularly as we've been plugging away experimentally in this field for a long time now. Until such drugs are developed we should utilise what is available and there is now abundant evidence for the presence of inflammation in PPMS, which has been previously ignored. Also immunosuppressants come in all sorts of flavours. The fact that Brutons Thymidine Kinase inhibitors are now in clinical trial for MS is to me at least, the source of much excitement and I'm sure they can have a positive role in PPMS.
      Then again I try to be a glass half full kinda guy.

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    2. Re: "The sad thing once a person becomes unemployed their worth to society drops."

      Very sad, but some economic models include indirect costs, i.e. loss of employment and social costs that increase with disability. Therefore the more disabled a person becomes at an economic level their worth drops. These are average effects and refer to groups not individuals. The bean counters are hard as nails.

      This same principle holds for insurance payouts; the younger you are the bigger the payout. The older you are the smaller the payout.

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    3. However, they seem to go crazy for Alzheimers lately (of course many more patients there)

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    4. Yes, bean counters, the folk who know the price of everything, and the value of nothing.

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    5. Hello MD2, I can't find details of the trial on Bruton's thymidine kinase inhibitors. This is not Mastinib, something else?

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    6. evobrutinib

      https://www.merckgroup.com/en/search.html#query%3AMerck%20Announces%20Positive%20Phase%20IIB%20Results%20for%20Evobrutinib%20in%20Relapsing%20Multiple%20Sclerosis%2Cpage%3A0%2Cbusiness%3Aall%2Clanguage%3Aen%2Ccategory%3Aall%2Ctype%3Aall

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  9. Glad ProfG is a glass half full type of chap

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    1. This allegorical image of a glass half full/empty is far too simplistic, doesn't even make sense, because it does not work on the level of the individual. One individual with progressive MS may be happy on a DMD which works out for them, another may find that it doesn't help much, impacts their quality of life, or even gives them a life-changing side-effect.

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  10. CFS-NFL is this easy to test for? If it is positive could it confirm MS or it it high in others diseases too?

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    1. Easy to test for. Our lab offers a service to other centres.

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  11. Re "there is a strong case for doing trials on combined populations of so-called advanced MS. In other words, we should combine PPMS and SPMS populations into one study"

    Isn't it true that many of the current DMTs would never had been licenced if the populations had been combined?

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    1. This exists because Pharma salami-sliced up MS into 3 diseases so that they could get INFbeta licensed under the orphan drug act with one trial, i.e. RRMS, SPMS and PPMS all had less than 200,000 people with the disease in the USA.

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    2. How do want combined population trials to be recruited and conducted - with a proportional mix of RRMS/ppms/spms? (As currently defined)
      Or without bothering about frequency of relapses at all?

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  12. Re "the therapeutic window remains open throughout the course of MS"

    Even in older patients?

    You've had many posts about how treatments are/become ineffective when patients are over 50 years old

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    1. The age phenomenon was assessed using the EDSS and not the 9HPT. Yes, age plays a role in MS; MS brings on premature ageing regardless of if you have relapse-onset MS or PPMS.

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    2. "You've had many posts about how treatments are/become ineffective when patients are over 50 years old"

      Because those treatments are not really active agents..the onus is still on the body to recover through plasticity of brain reserve which always declines w/age.

      The ebv tcell therapy from atara bio seems the only therapy
      that worked to stop PPMS progression and equally worked on
      60 year olds. If it stops PPMS progression that tells you
      it really gets to the heart of the disease. Don't think
      any PPMS patient has ever gone down the EDSS scale let alone
      a 60 y/o PPMS from 5.0 to 3.5 scroll down 3/4 to see study

      https://imgur.com/niGAJWi

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    3. Post 50 years of age is clearly at the forefront of a lot of minds.

      Prof G will you kindly chase up on the analysis of the study shared on the blog back at the beginning of February this year.

      Thanks very much.

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  13. "Studies looking at the pathology of progressive MS show without doubt that PPMS is inflammatory"


    The significance of C3d1 microglial clusters formation
    is an important question. Their presence in the chronic but
    not acute disease stage, their localization on injured axons,
    their association to local production of C3 by neurons, their
    occurrence in the absence of antibody, C1q or MAC deposits,
    suggest that they are not part of an acute immune attack
    against myelinated axons, but may represent a physiological
    process linked to the progressive disease stage such as the elimination
    of myelin debris or transected axons or terminal axonal
    ovoids (Trapp et al., 1998), the protection against energy deficiency
    (Nijland et al., 2014) or the uptake of extracellular glutamate
    (Nakajima et al., 2001) for protection against
    glutamate-mediated excitotoxicity (Geurts et al., 2003). Notably,
    our observations suggest that C3d1 microglial clusters formation
    is a transient phenomenon, as it does not occur in
    pathologically inactive disease where processes such as axonal
    injury are essentially dying out (Frischer et al., 2009).
    Altogether, our data support the noninflammatory nature
    of C3d1 microglial clusters, pointing to the possibility that they
    are involved in the physiological removal of irreversibly damaged
    axons. This process is substantially different from the acute complement
    attack against myelinated axons, seen in actively demyelinating
    lesions. In such scenario, pharmacological interventions
    to halt C3d1 microglial clusters formation might have no effect
    in the propagation of chronic MS pathology. Our study adds to
    the identification of physiological and/or pathological processes
    in MS, ultimately guiding therapeutic choices.

    This paper says a diferent thing


    Obrigado

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    1. Not it sure it does. Microglial clusters occur in both relapse-onset and primary progressive MS. Abnormal 'normal appearing white matter', where some of these clusters are found, occur in both.

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    2. This paper is referring to late vs. early disease. The more damage you get the more innate immune (microglial) activation that occurs. This is elegantly shown with PET imaging (PK11195).

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    3. In acute MS cases with either pattern II or pattern III
      lesion pathology we found no evidence of microglial clusters
      or linear deposits of C3d, suggesting that clusters formation
      is independent of active demyelination. In the periplaque
      white matter, microglia showed a sparse distribution and a
      resting morphology, as indicated by the thin appearance of
      IBA-11 ramifications and the low immunoreactivity for CD68
      (Fig. 2N,O).

      Did you read the paper?

      Obrigado

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  14. https://www.ncbi.nlm.nih.gov/pubmed/27778395

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    1. Glia. 2017 Feb;65(2):264-277. doi: 10.1002/glia.23090. Epub 2016 Oct 25.
      Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: Implication for disease pathogenesis.
      Michailidou I1, Naessens DM1, Hametner S2, Guldenaar W3, Kooi EJ3, Geurts JJ3, Baas F1, Lassmann H2, Ramaglia V1.
      Author information
      Abstract
      Microglial clusters with C3d deposits are observed in the periplaque of multiple sclerosis (MS) brains and were proposed as early stage of lesion formation. As such they should appear in the brain of MS donors with acute disease but thus far this has not been shown. Using postmortem brain tissue from acute (n = 10) and chronic (n = 15) MS cases we investigated whether C3d+ microglial clusters are part of an acute attack against myelinated axons, which could have implications for disease pathogenesis. The specificity of our findings to MS was tested in ischemic stroke cases (n = 8) with initial or advanced lesions and further analyzed in experimental traumatic brain injury (TBI, n = 26), as both conditions are primarily nondemyelinating but share essential features of neurodegeneration with MS lesions. C3d+ microglial clusters were found in chronic but not acute MS. They were not associated with antibody deposits or terminal complement activation. They were linked to slowly expanding lesions, localized on axons with impaired transport and associated with neuronal C3 production. C3d+ microglial clusters were not specific to MS as they were also found in stroke and experimental TBI. We conclude that C3d+ microglial clusters in MS are not part of an acute attack against myelinated axons. As such it is unlikely that they drive formation of new lesions but could represent a physiological mechanism to remove irreversibly damaged axons in chronic disease. GLIA 2017;65:264-277.

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  15. Why do relapses stop when the progressive phase begins (in most cases)? Why don't they co-exist till the end?

    Why high doses of Biotin can bring relapses to progressive patients. How can it be explained?

    You had said at an older post that if we would find something that could stop both phases we could claim that MS is one disease. For now, only HSCT might be doing that if done at RRMS. But the treatment is too "total" to help us understand the specific mechanisms.


    In my opinion the problem starts by separating MS to inflammatory - non inflammatory. We just cant spot the problem behind it yet.

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  16. If you consider PPMS to be „low level“ RRMS (below the MRI detection level) then why do you intend to treat it with some powerful induction therapies such as Mavenclad, Ocrevus,.. instead of a less potent treatment?

    I thought Betaferones were already approved for treatment of SPMS. Why hit harder?

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  17. There are different kinds of MS but not the clinical kinds we normally speak of.

    We have patients without oligoclonal bands. Others with IgM, IgG or IgA. There are different lesion patterns and different response to medication. The heterogeneity is enormous.

    Different kinds of MS should be studied separately.

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