MSers want a cure. However, even if we have an MS cure in hand we may not prevent or reverse progressive disease. How can this be?
Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or it can damage nerves and leave them functioning, but the resulting damage primes them to die off in the future; I call this delayed 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, etc.
Clearly, anti-inflammatory drugs that prevent new lesions 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 delayed die-off of neurons and axons.
What protects you from entering the clinically-apparent secondary progressive phase of the disease is reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I suspect that MSers, who have been treated with highly-effective DMTs and 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 the future. In other words, they were treated with DMTs too late to prevent SPMS. This is why we keep pushing the message ‘early effective treatment’ is the only way to prevent secondary progressive MS.
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 therapies to target the delayed neurodegenerative processes referred to above. The latter includes avoiding or reversing 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.).
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 my drive progressive MS. The exception may be natalizumab. There are several reports of MSers 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.
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 to test a therapy for myeloma (malignant plasma cells) in MS. Can we scrub the MS brain free of plasma cells?
CoI: multiple
So why are people pushing for treatment like ocrelizumab for ppms and siponimod for spms? Surely these will not work based on these comments.
Also what is the point of trials for those in the progressive phase and potentially in wheelchairs if what you suspect is true?
I can see the point if your progressive disease is still active to try and stop new activity but some of the trials for progressive are not requiring proof of activity.
Ocrelizumab and siponimod do work, but not that well. They are only moderately effective in slowing down worsening. They are however a start. What we now need is to build a pyramid of treatments to tackle the mechanisms that cause worsening in the post-inflammatory state, i.e. neuroprotectives and remyelination & neurorestorative therapies.
Fair enough that is obviously what we need but at the moment we do not have the full set of drugs which creates the pyramid so what is the point of subjecting yourself to potential side effects for drugs that are only marginally effective at best.
Likewise what is the point of trials for people in wheelchairs using drugs which may probably only be marginally effective which will then result in no form of approval to roll the said drug out.
Surely you should wait and try and create trials using potential protective and restorative drugs along with the anti-inflammatory established drugs EG ocrelizumab or cladribine.
I agree with you. Small beginnings can be the start of something big. Never give up hoping .
If the damage has been done to the nerve fibres and the CURE won’t repair damage, making SPMS a “shoe in”. Why is HSCT not the solution to reboot nervous system?
HSCT is just an anti-inflammatory therapy and is no different from other anti-inflammatories. HSCT prevents new lesions from forming. HSCT does nothing to repair previous damage.
The problem with HSCT is that some of the chemotherapy agents used are neurotoxic and damaged nerve fibres are more susceptible to the neurotoxicity of these agents and explains why some MSers with more advanced disease do worse after HSCT. This is why a large number of bone marrow transplant units don’t treat progressive MS with HSCT.
I am then guessing that natalizumabers are excluded from SIZOMUS since they won’t meet the 4th criterium?
Tony
No they are not!
But they have to have OCBs at baseline to participate.
Tell me there are good news for Cladribine as Natalizumab. Is there a chance that is going to work just as good as Natalizumab?
Prof G,
Thanks for this summary. My take on your piece is that (1) MS is way more complicated than previously thought and (2) once you hit the progressive stage you’re a gonner (treatments aren’t going to have much effect.
My position is 11 years since first Alemtuzumab infusion. I remain stable – no relapses, no activity on annual MRI, stable EDSS. I exercise and follow the advice of your brain health matters initiative. I don’t expect personal advice (and you wouldn’t give it), but how does my sort of case fit into your thinking. Is progressive MS inevitable? I was hoping to remain stable for 15 years as this was the time at which you thought it might be possible to assess whether Alemtuzumab (and other highly effective therapies) offered a potential cure for some. Have you changed your view on this?
Great question!
I am luckily in the same box as you, but have learned (since 2016) that was is now called smoldering is the cold reality. Progression as you think of it (SPMS) is inevitable. Progression as MD things of it is ongoing.
We are just buying a house now and I am already laying out plans for a hydraulic lift (EDSS of 52 years) don’t go well together, but brain reserve capacity helps.
Re: “once you hit the progressive stage you’re a gonner (treatments aren’t going to have much effect.”
Only partially correct. They will have an effect, but only less than if the disease was treated early. We don’t give up on anyone. This is why we are doing trials to protect upper limb function in MSers with advanced MS (wheelchair users).
Re: “I was hoping to remain stable for 15 years as this was the time at which you thought it might be possible to assess whether Alemtuzumab (and other highly effective therapies) offered a potential cure for some. Have you changed your view on this?”
No, I have not changed my view on this. You may be one of the lucky ones who was treated early enough before too much damage was accrued and the immune system had set-up shop within your brain and spinal cord.
Let’s hope you remain NEDA and stable.
Thanks. Is there anything else I could do (treatment wise) as an insurance to push back progressive disease / possible worsening?
If the disease did reignite I was told a third infusion was an option. However it’s all gone quiet on the review of Alemtuzumab as a first line therapy. Any idea when we might hear something?
(smoking, co-morbidities, lack of exercise, infections, etc.)
You forget one
High BP, rising BP between ages 36-53 associated with smaller brain volume, white matter lesions in later years
https://medicalxpress.com/news/2019-08-high-bp-ages-smaller.html
How could we forget High blood pressure….of to take my pill as we speak
I hope you are making lifestyle and diet adjustments for your high blood pressure and not just pill-popping.
High BP is comorbidity.
Well that’s me well and truly screwed!
Mine was something like 200/90 just before I had an gastroscopy and as always they put the HBP down to white coat syndrome and nobody ever does anything about the constant high readings. I can’t see why they ever bother taking it to be honest!
So where does the PoNS (portable neuromodulation stimulator) device fit in all this?
It doesn’t.
“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, etc.”
Great post but these have been known about for decades and repeatedly mentioned for over a decade by this website yet zero approved treatments to attack this aberrant innate immunology or to actually improve the clinical condition of a progressive MS patient.
Where is the proof that these non-specific intrathecal plasma cells, which are present in many other CNS conditions like stroke, are pathological and not just part of a cleanup response by the immune system to a virus or some other APC?
At best, immunosuppressants may delay deterioration slightly and in a few years neurodegenerative preventative drugs may slightly augment this. Where are the products that actually improve the QOL in a progressive MS patient that can help them regain some sort of semblance of a normal productive life?
A progressive stage MS patient is much like the unfortunate forgotten post-polio syndrome patient. There is absolutely no urgency in the MS research world as highlighted by studying treatments sequentially, instead of together.
Where is the proof that the plasma cells are important….you have to get rid of them and see if something happens. This is the current plan and we are ready to go.
As for nothing for progressive MS, I disaggree but the neuros have to work out how best to show it.
MD, I respect your very informative and humorous posts but this makes no sense to me. Please explain the following re: plasma cells/IgG synthesis:
Intrathecal oligoclonal IgG synthesis is non specific for MS, not pathognomonic. It occurs in neoplasm-myeloma, lymphoma, etc., other autoimmune conditions like SLE, sarcoidosis, etc., infections like Lyme disease, syphilis, etc., stroke and subarachnoid hemorrhage.
This would indicate that IgG synthesis is a response to damage that already has occurred in the CNS. From what I read, even PML also causes an increase in IgG synthesis indicating that IgG is a response to damage that has occurred already in the CNS or a downstream reaction which will not be halted with eradication of plasma cells.
A trial is planned by NDG and ProfG to see if they can inhibit plasma cells and intrathecal Ig that we have suggested may activate glial cells. You don’t need specificity
Likewise, neurodegeneration is not specific for MS and it may be a consequence of the process
Re: “yet zero approved treatments to attack this aberrant innate immunology or to actually improve the clinical condition of a progressive MS patient.”
That is because Pharma has been chasing the low hanging fruit. It is not for lack of trying. We, the academic community, have been involved with a lot of add-on neuroprotection studies and some of these are positive. Watch this space; big pharma will get on board as soon as the risks of failure seem less.
Which add-on therapies have appeared to have positive preliminary results?
So, what’s the process in PPMS, where there were never any active lesions (or only one or two at the onset), and despite aggressive treatment with Tysabri, Ocrevus and Lemtrada, the patient experiences a rapid, downhill course of devastating spinal cord MS? Seems that this almost exclusively neurodegenerative form is quite different in nature than the disease process of SPMS.
The fact that, after 35 years of MS and a brain and spine riddled with hundreds of lesions, I have advanced SPMS is completely expected. What it doesn’t explain is why after numerous episodes of Optic Neuritis and complete blindness 35 years ago, my optic nerve, according to my opthalmologist is perfectly healthy and my vision is perfect.
You can loose quite a few nerves in the optic nerve before things come mission critical, but you have the power to repair and the younger you are the better the repair. You can have many lesions in your brain and not notice it but have one devastating lesion in the wrong bit of the spinal cord and you will suffer the consequence. Next question is it true that PPMS never have active lesions, I doubt it as there are active lessions in most people
Just wanted just to say (ahem, on behalf of everyone here). Thanks for posting AND moderating the post so eloquently.
It is most impressive for long term followers of this blog like myself how the quality and depth of questions keeps improving year-on-year.
This is possibly a good indicator of the “efficacy” of this blog as a multi-level educational medium. (I say Educational as it clearly goes way beyond Informational)
Tony
thanks for the kind words on behalf of the team
Which add-on therapies have appeared to have positive preliminary results?
ectrims2019
Boy, what a depressing post, it is what it is but basically, those of us in SPMS phase who have lost function are doomed. No one ever talks about stem cell trials (there are a couple of FDA ongoing trials, Tisch center and brainstorm Therapeutics at Mayo Clinic recruiting for SPMS). To just always highlight the obvious, treat early and treat aggressively, leaves out the many other patients whose barn door has closed. We need to channel more resources to reversing disability, not just stopping it. I don’t want to continue living with a hopeless future as I have already lost enough