Don’t mention the C-word as it raises unnecessarily high expectations is what many of my colleagues say. I don’t agree with them. Showing we have cured, or not cured, MS is how we will ultimately test the hypothesis that MS is an autoimmune disease.
People with MS (pwMS) want a cure. However, even if we have an MS cure in hand we may not prevent or reverse progressive disease. Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or inflammation sets up processes that result in delayed worsening. The acute inflammatory MS lesion also damages axons and neurons but they manage to remain functioning albeit in a vulnerable state. However, this damage primes these axons and nerves to die off in the future. I like to call this delayed post-inflammatory neurodegeneration.
The mechanisms that result in delayed neurodegeneration of nerves or smouldering MS are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals (oxygen and nitrogen radicals), premature ageing, intrathecal plasma cell production of pathogenic autoantibodies, persistent viral infection, etc.
Clearly, anti-inflammatory drugs that prevent new lesion formation, such as natalizumab, alemtuzumab and ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that have damaged many nerve fibres, even if you go onto a highly effective DMT that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future. This is why did the PROXIMUS trial and are promoting the OXO trial; add-on neuroprotective drug to try and modify the primed but delayed die-off of neurons and axons in the future.
What protects you from entering the “clinically-apparent” secondary progressive phase of the disease is your reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I suspect that pwMS, who have been treated with highly-effective DMTs and who have now become secondary progressive, had a low reserve capacity and a large number of damaged nerve fibres that had been primed to die off. In other words, they were treated with DMTs too late to prevent SPMS in the vanguard pathway (the neuronal pathway with the most damage). This is why I keep pushing the message ‘early effective treatment’ is the only way to prevent secondary progressive MS.
The same processes happen in PPMS the only difference is pwPPMS don’t have the earlier relapses that bring them to the attention of the medical profession in the initial stages of the disease.
There are two conclusions to be drawn from these observations; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, and (2) we need additional add-on neuroprotective, remyelinating and neurorestorative therapies to target the delayed neurodegenerative processes referred to above.
In addition to this, we need to avoid and/or reverse any other factors that prematurely age the nervous system. The ageing hypothesis of progressive MS is a major factor that underpins our Brain Health campaign, which targets non-specific factors that have been associated with more rapid progression in MS (smoking, co-morbidities, lack of exercise, infections, etc.). Common to all these factors is that they reduce your reserve and hence bring forward and speed up progressive MS.
So unless you are rendered NEDA early in the course of your disease it may not prevent you from entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, our licensed DMTs don’t kill long-lived plasma cells that continue to make intrathecal (within the CNS) antibodies that may drive progressive MS. The exceptions may be natalizumab and cladribine.
There are several reports of pwMS on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a ‘niche’ or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard.
A recent report from Poland showed that about 50% of pwMS treated with intravenous cladribine more than 10-years ago had lost their oligoclonal IgG bands and were more likely to be stable than the those who have not lost their OCBs. There is old and new data emerging suggesting that the immunoglobulin is present in the cerebrospinal fluid of pwMS is toxic to oligodendrocytes (cells that make myelin) and can stimulate microglia. Just maybe the immunoglobulins are responsible for the slowly expanding lesions (SELs) or the subpial grey matter lesions that are such an important part of progressive MS
To target plasma cells, which are long-lived, we will need add-on therapies. This is high on our list of priorities and we are starting the SIZOMUS trial, COVID-19 permitting, to test a therapy for myeloma (malignant plasma cells) in MS. We are also looking at the effects of cladribine in a similar way (CLADRI–PLUS and CLAD-B studies) and we also want to look at the impact of very early treatment of MS with natalizumab as well (ATTACK-MS study). We also have a longish list of other potential therapies we would like to try as well, but we need help with this, i.e. funding, colleagues to share the workload and potential Pharma interest to give us access to some of the compounds we have identified as potentially promising.
Our challenge and objective are to scrub the MS brain free of B-cells and plasma cells!
Some people don’t buy into this hypothesis, but it is also supported by the observation that pwMS who receive higher doses of ocrelizumab do better than those receiving lower doses. I think that this may be related to more CNS penetration of ocrelizumab and is why I have proposed that Roche do a double-dose or DODO study. In relation to the DODO study, it is not necessarily about giving double-dose ocrelizumab indefinitely, but only early on as induction therapy and then to explore post-induction safer maintenance therapies (BTKi or teriflunomide). Please see the iTeri and iBruT studies in the slide show below. I can’t stress how important these observations are and they have made me question whether or not we have optimised the dose of both ocrelizumab and rituximab and other emerging anti-CD20 therapies.
So yes, we may be able to cure you of MS with IRTs but you may not realise it depending on when in your course you are treated. So as you can see we as an MS community have a lot still to do when it comes to improving disease outcomes of people with MS and yes we need to mention the C-word. We need to define what a cure means and how to look for it so that we can declare victory or not.
CoI: multiple
PS there is quite a lot chatter going on Twitter in relation to this post.
https://platform.twitter.com/widgets.jsProf G has been told not to mention the C-word as it raises too many expectations. However, if we don't define and look for an #MScure we won't be able to move beyond where we are today. Do you agree? #ResearchSpeak https://t.co/ZiEa7HfeHO pic.twitter.com/2bFqZSxR1v
— Gavin Giovannoni (@GavinGiovannoni) June 1, 2020
Thank for the post and for the many ideas to improve therapies and for the many advices and information you give to pwMS.
I was wondering about combination of Anti-CD20 depletion plus cladribine given in sequence with the goal of depleting circulating B-cells and then try to kill the survivors in the CNS with a larger amount of Cladribine that has not been uptaken from circulating CD20+ cells… does it make some sense for you? Maybe too many expected side effects like T cell depletion?
If a (immuno?)proteasome inhibitor was put on top of an extended depletion platform this treatment could result in something like a low risk reset of immune system compared to AHSCT. I am eager to see SIZOMUS trial results. Is there a planned date to start recruiting? Do you expect people on IRT/Anti-CD20 to do better? (I would)
Concerning the plasma cells effects side, do you think that antibodies in CNS may prevent remyelination hiding signal surface molecules on damaged tissue from oligodendrocytes detection impeding them from doing their job of detecting and repair damage? Would this fit with observation of natural damage repair in early phases of the disease?
Last one, what do you think is needed to do to share the workload of so many studies with other MS centers? Why the MS neurologists community seems not moving as a team to try at least small trials like these without big pharma support/involvement? Is it the amount of money needed? Multiple local paperwork to do? Extended use of off-label treatments/regimens and related required authorizations?
Prof G,
Have you changed your view recently? There is no mention of EBV in the post above. I thought you were proposing that progression was there from the start – EBV in the brain with the innate immune system killing off nerve cells and the external immune system (focal inflammation) just a response and not the real MS.
I’ve lost count of the various trials (completed and planned) aiming to identify add on therapies. What’s your best guess as to when we will get one available? If you had MS and had been treated with an IRT what sort of drug would you hope for first – remyelination drug, something to tackle hot microglia? The list of targets above is very long – I wonder if it’s a good future for MS researchers rather than a good future for MSers.
Yes, EBV is hidden in the text under the reference to viral infection. The induction-maintenance trials I refer to are targeting EBV. Kill the memory B-cell and then let them come back in the presence of an antiviral, i.e. teriflunomide.
Is there a planned trial to test this??
Yes, pending a grant application and funding.
Funding or not, there are already pwms that have developed and implemented DMT treatment plans (in consultation with their neurologist) that are very similar to some of Prof. G proposed studies. Unfortunately, there are no platforms or avenues for us to report results. Stopped Ocrevus due to severe adverse reactions (both during the infusion and subsequently thereafter) and started Teri as a second line treatment. So far so good……..
“come back in the presence of an antiviral, i.e. teriflunomide”
Seems like it has an effect on EBV…but no sure it’s that great..
“However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown.”
https://pubmed.ncbi.nlm.nih.gov/28574826/
Re: “However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown.”
Yes, it is a hypothesis that needs to be tested in a controlled trial. This is how science works; unlike religion when you believe something works and that’s that.
Re: ” If you had MS and had been treated with an IRT what sort of drug would you hope for first – remyelination drug, something to tackle hot microglia?”
If you get treated early enough you won’t need add-on therapies for remyelination, neuroprotection or neurorestoration. But you may need something to keep the virus at bay. I think neuroprotection is more important and then remyelination.
“If you get treated early enough you won’t need add-on therapies”
People fail hsct and alem….Even treated within 3 years of diagnosis people fail hsct…facebook alemtuzumab is full of nonresponders.
Then you have people disease free 11 years hsct who fail treatment.
And can’t see how taking copaxone or beta seron would’ve helped any.
Re: “And can’t see how taking copaxone or beta seron would’ve helped any.”
Without a trial, you are simply guessing. This is why hypotheses and controlled trials are so important.
Trials are time/money consuming..you need to propose a mechanism…hypothesis itself is dime a dozen.
Thanks Prof. G. for the excellent article. Do all these good news about Natalizumab still apply to anyone who takes natalizumab at 6-week intervals? Especially when you say: “There are several reports of pwMS on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a ‘niche’ or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard.
As I asked you, do you think these positive effects remain intact even with infusions of Natalizumab every 6 weeks?
Thanks so much
The data on loss of OCBs in pwMS on natalizumab needs more work. It has not been reproduced in all studies. Yes, you are right that EID (extended interval dosing) may blunt this effect. Lots still to study in relation to natalizumab and MS. We will hopefully be testing the early treatment hypothesis in relation to natalizumab.
Thanks for the answer Prof. G. I have been on EID for two months (natalizumab). I don’t know how you think but even if some effects of Natalizumab can be mitigated, on the cost / benefit balance of choosing EID, it seems to me that the benefits (PML problem) are certainly predominant.
EID is a bit like saying: In medio stat virtus ….
Thank you Prof G for a very informative post. I dare not get excited but certainly the hope for the future looks brighter with these positive ideas. Thank you to you and all your colleagues
I realise that being in the middle of the largest pandemic the world has seen in over a century is an ideal time to post suggestions on MS treatment (NOT).
I’ve just had an article shared with me – not a scientific publication in and of itself but it links out to plenty of studies and has references:
https://theconversation.com/autoimmune-diseases-we-discovered-how-to-turn-white-blood-cells-from-attacking-the-body-to-protecting-it-140601
It’s a bold claim. And there isn’t much of a therapy associated with it – it’s all still very much research rather than a product. But I’d love to know your thoughts – could there be a viable treatment in there somewhere?