Isn’t there a risk that this trial could be overtaken by events? I’m guessing the trial would take 7-10 years to complete. If one of the BTK inhibitors showed good effect on progression / smouldering MS, then progressive patients would want to be on that drug rather than risk being on the placebo on this trial. Ditto for the drug being tested on the Sizomus.
PS I thought you were focusing on EBV (anti-virals / vaccines).
Personally feel like I’m doomed with all this talk of PIRA , when I was diagnosed 6 months ago I thought being on a high efficiency dmt (tysabri) was the best option, am I taking all the associated risk with taking this dmt only to still get progressively worse at the same rate as I would with a lower risk dmt
In my head that is the unanswerable question. I’ve started Siponimod, but I can never know, for me personally, how my SPMS would have progressed if I hadn’t taken it. I have to trust the research that it gives me the chance to be, in simplistic terms, something like 31% better with it than without it. You might still get worse, but hopefully more slowly and not at the same rate as with a different DMT or no DMT.
Yes, standard MRI monitoring for focal lesions is not enough, and we will need additional biomarkers of smouldering MS in the future. Some of these biomarkers will be more advanced imaging markers.
Thank you for replying. It’s cold comfort though. I will do y2 cladribine in July and the way the healthcare system is in my country I don’t even know if I’ll be able to get regular MRIs to be monitored after that. Should neurologists be using neuro filament light levels to monitor disease activity after IRT? What would be the frequency? Is zero the only acceptable result?
When I had MRI's taken, the technicians would almost immediately take the pictures after injecting the gadolinium. And for years my films would look almost exactly the same with the same lesions In the same spots, and illuminating or not lighting up in the same spots, as well as enhancing lesions and black holes never changing size; which didn't make any sense. Basically everyone gaslighting me in a way, and it didn't seem anyone was taking me seriously enough when I could tell my CNS was unmistakably degenerating while everyone was telling me that I was stable. I wish I had more resolve to have pushed harder instead of accepting my doctors talking down to me, and telling me I didn't understand enough. NEIDA Might have been acceptable 20 years ago, but we all know much more today to actually be using that measurement singly as a stopgap.
The protocols usually allow some non-Gd-sensitive images before doing the repeat T1 post-Gd/contrast image. For example, the Gd effect on T2-weighted images is generally negligible. So, the protocol is to have your pre-contrast T1 Images and other Gd-sensitive sequences/images done before the Gd is administered. The 10-minute gap refers to the second repeat post-contrast T1 sequence.
That's what I was referring to; the second set of images. I would have a set of MRIs taken, then the second set they would inject gadolinium and almost immediately take another set of MRIs. Sorry, I should've been more explicit about that.
At the age of 57, I am probably too old to take part. Hypothetically, I don’t fancy AHSCT, it’s a gut reaction based on a risk versus benefit argument in my head. I am not unhappy with my life with an EDSS of 3.5 so do I see enough benefit to mitigate the risks of AHSCT? Probably not. I would have to do some research into it if I was offered it. This feeling is exacerbated
As for your flow diagram about the evolution of MS lesions, this is what I get from it:
Old Pre-Gd lesions become new Gd- enhancing lesions. 80% of these become new T2 lesions. I assume this means that 20% do not progress to be new T2 lesions and remain as Gd enhancing lesions.
If this interpretation is correct, how do 80% become acute PRL, 50% become acute transient black holes and still more disappear at the T2 stage. So 130% of the 100% of lesions available evolve along these two paths? How?
It then looks like 50% of acute transient black holes become chronic, so 50% don’t?, and 25% of chronic transient black holes become SELs. In addition tiny, too small to detect, SELs that have nothing to do with GD-enhancing or new T2 lesions add to the SEL count, as do a small number of SELs that were originally classified as PRLs. Possibly all of these eventually stop expanding?
The other possibility is that the new T2 lesions become Acute PRLs but only a small number of these (5 to 10%) become chronic and ultimately ex-PRLs. What happens to the rest? And finally, is there two way traffic between chronic PRLs and the bottom of the SELs circle, or is one of the arrows incorrect.
On the subject of lesions in the spinal cord, I have wondered why my new neurology team are only planning to request MRI scans of my head in future. My only scan so far for them was brain and whole spine to establish a baseline. This is in contrast to my old team who started off, 14 years ago, just scanning my brain, then requested brain and C-Spine and most recently brain and whole spine. This is a very small concern for me, given that they could tell me that my hands are most likely getting worse because I have a lesion exactly where the nerves to my hands leave the spine, which they wouldn’t know from just a brain scan. However, overall the move has been a good one with the benefit of actually being treated with Siponimod and having a team of HCPs who willingly answer my questions, even when they are asked via email!
That should say: “This feeling is exacerbated by having no desire to be old, bed-bound and totally dependant on others like my Mum in her later years. That’s not to say that she was unhappy. Fortunately she was very content in her own world.
May I ask what your opinion would be if you want to address EBV via an antiviral such as tenofovir/Emtricitabine (Truvada) but are going to do HSCT? Does truvada clash with HSCT in any way putting your organs such as kidney and liver at more risk of adverse reactions? The same with BTKi's. Do BTKi's have interactions with Truvada that are unfavourable?
Is this trial you are proposing a combination therapy study to address inflammation via HSCT and then smouldering via BTKi post HSCT? I am going to do HSCT shortly, perhaps tolebrutinib would be something to consider post HSCT? Or if your neurofilament testing is normal post HSCT there might be no need to take any BTKi's?
Yes, the AHSCT addresses any residual focal inflammation, as most subjects eligible for this trial with a PIRA event will have been on a high-efficacy DMT. The AHSCT is then followed by a CNS penetrant therapy targeting smouldering MS.
I am not sure AHSCT will be sufficient as a large number of patients with PIRA (progressive MS) who have AHSCT continue to get worse.
Do you mean HSCT for RRMS could be sufficient for long-term remission without ever encountering PIRA for life meaning no need for BTKi? Alternatively, people who have HSCT while they are at the PIRA stage are going to need a BTKi because HSCT is not likely to stop PIRA. Is that what you mean Prof G? So once you cross that PIRA rubicon there is no going back.
Re: "Do you mean HSCT for RRMS could be sufficient for long-term remission without ever encountering PIRA for life meaning no need for BTKi?"
Yes, a minority of pwMS who are treated with AHSCT and alemtuzumab early in the course of their disease (<2 years after symptom onset) are in long-term remission (>15 years) with no signs of smouldering MS. They may even be cured of having MS.
This post and its responses makes me feel rather desperate. So many of these therapeutic proposals are guesses that probably are not going to provide clear results and will rase the question, lurking in the confusion, what is actually happening in the CNS tissues? What are the cellular and immune mechanisms that can account for the clinical events, including progression and smouldering?
I am now addressing myself; 'go to the tissues they will tell you what the answer is', and consequently what therapeutic opportunities that can cut through the enigma. The current therapeutic experiments cost very much more than laboratory investigations to answer the question, what is going on the CNS in MS?
Isn’t there a risk that this trial could be overtaken by events? I’m guessing the trial would take 7-10 years to complete. If one of the BTK inhibitors showed good effect on progression / smouldering MS, then progressive patients would want to be on that drug rather than risk being on the placebo on this trial. Ditto for the drug being tested on the Sizomus.
PS I thought you were focusing on EBV (anti-virals / vaccines).
I am - BTKi are very effective anti-EBV drugs; working out to use them is of interest.
Personally feel like I’m doomed with all this talk of PIRA , when I was diagnosed 6 months ago I thought being on a high efficiency dmt (tysabri) was the best option, am I taking all the associated risk with taking this dmt only to still get progressively worse at the same rate as I would with a lower risk dmt
In my head that is the unanswerable question. I’ve started Siponimod, but I can never know, for me personally, how my SPMS would have progressed if I hadn’t taken it. I have to trust the research that it gives me the chance to be, in simplistic terms, something like 31% better with it than without it. You might still get worse, but hopefully more slowly and not at the same rate as with a different DMT or no DMT.
So what does this mean for being monitored after an IRT? That MRI monitoring only isn’t enough?
Yes, standard MRI monitoring for focal lesions is not enough, and we will need additional biomarkers of smouldering MS in the future. Some of these biomarkers will be more advanced imaging markers.
Thank you for replying. It’s cold comfort though. I will do y2 cladribine in July and the way the healthcare system is in my country I don’t even know if I’ll be able to get regular MRIs to be monitored after that. Should neurologists be using neuro filament light levels to monitor disease activity after IRT? What would be the frequency? Is zero the only acceptable result?
Its base line spinal cord area
That counts
Not the drug
https://www.sciencedirect.com/science/article/pii/S2211034824003225
What would be the "add-on CNS penetrant therapy to target smouldering MS"?
A BTKi (e.g. tolebrutinib), proteasome inhibitor (e.g. Ixazomib), etc.
I would join if you were to add an alemtuzumab arm.
Aren't proteasome inhibitors neurotoxic?
Yes, which is why they are dosed intermittently.
What is your opinion of mitoxantrone
It isn't easy to justify its use now that we have other treatments for active progressive MS. But it still has a place in resource-poor environments.
https://msselfie.co.uk/dmtsdetail/mitoxantrone-detail/
This post is very disconcerting.
When I had MRI's taken, the technicians would almost immediately take the pictures after injecting the gadolinium. And for years my films would look almost exactly the same with the same lesions In the same spots, and illuminating or not lighting up in the same spots, as well as enhancing lesions and black holes never changing size; which didn't make any sense. Basically everyone gaslighting me in a way, and it didn't seem anyone was taking me seriously enough when I could tell my CNS was unmistakably degenerating while everyone was telling me that I was stable. I wish I had more resolve to have pushed harder instead of accepting my doctors talking down to me, and telling me I didn't understand enough. NEIDA Might have been acceptable 20 years ago, but we all know much more today to actually be using that measurement singly as a stopgap.
The protocols usually allow some non-Gd-sensitive images before doing the repeat T1 post-Gd/contrast image. For example, the Gd effect on T2-weighted images is generally negligible. So, the protocol is to have your pre-contrast T1 Images and other Gd-sensitive sequences/images done before the Gd is administered. The 10-minute gap refers to the second repeat post-contrast T1 sequence.
That's what I was referring to; the second set of images. I would have a set of MRIs taken, then the second set they would inject gadolinium and almost immediately take another set of MRIs. Sorry, I should've been more explicit about that.
Hi Prof G, I didn't see a link to the short survey you referred to. I think it is missing in the article. Can you post here? Cheers, Natasha
https://docs.google.com/forms/d/e/1FAIpQLScdz_trJbLTYWkm8rkPwYryjLuCI4cfqXwRIBKW3xA9OSjnEg/viewform
It is at the end of the newsletter. Thanks.
we need to forget the relapse 'idea' .
i remember you saying rrms was confected for fda. lets trumpet that very loud and clear!!
thanks for the spinal info.
i was started on kesimpta with study inc spine and head mri. now im getting spinal symptoms the spinal mris are stopped.
report says my ms stable - spinal stuff ignored
100% agreed!
At the age of 57, I am probably too old to take part. Hypothetically, I don’t fancy AHSCT, it’s a gut reaction based on a risk versus benefit argument in my head. I am not unhappy with my life with an EDSS of 3.5 so do I see enough benefit to mitigate the risks of AHSCT? Probably not. I would have to do some research into it if I was offered it. This feeling is exacerbated
As for your flow diagram about the evolution of MS lesions, this is what I get from it:
Old Pre-Gd lesions become new Gd- enhancing lesions. 80% of these become new T2 lesions. I assume this means that 20% do not progress to be new T2 lesions and remain as Gd enhancing lesions.
If this interpretation is correct, how do 80% become acute PRL, 50% become acute transient black holes and still more disappear at the T2 stage. So 130% of the 100% of lesions available evolve along these two paths? How?
It then looks like 50% of acute transient black holes become chronic, so 50% don’t?, and 25% of chronic transient black holes become SELs. In addition tiny, too small to detect, SELs that have nothing to do with GD-enhancing or new T2 lesions add to the SEL count, as do a small number of SELs that were originally classified as PRLs. Possibly all of these eventually stop expanding?
The other possibility is that the new T2 lesions become Acute PRLs but only a small number of these (5 to 10%) become chronic and ultimately ex-PRLs. What happens to the rest? And finally, is there two way traffic between chronic PRLs and the bottom of the SELs circle, or is one of the arrows incorrect.
On the subject of lesions in the spinal cord, I have wondered why my new neurology team are only planning to request MRI scans of my head in future. My only scan so far for them was brain and whole spine to establish a baseline. This is in contrast to my old team who started off, 14 years ago, just scanning my brain, then requested brain and C-Spine and most recently brain and whole spine. This is a very small concern for me, given that they could tell me that my hands are most likely getting worse because I have a lesion exactly where the nerves to my hands leave the spine, which they wouldn’t know from just a brain scan. However, overall the move has been a good one with the benefit of actually being treated with Siponimod and having a team of HCPs who willingly answer my questions, even when they are asked via email!
That should say: “This feeling is exacerbated by having no desire to be old, bed-bound and totally dependant on others like my Mum in her later years. That’s not to say that she was unhappy. Fortunately she was very content in her own world.
Nice
Study
Your graph is confusing
Remember Einstein
If you cant explaim your theory to a 6 year old
Your theory does.mean nothing
May I ask what your opinion would be if you want to address EBV via an antiviral such as tenofovir/Emtricitabine (Truvada) but are going to do HSCT? Does truvada clash with HSCT in any way putting your organs such as kidney and liver at more risk of adverse reactions? The same with BTKi's. Do BTKi's have interactions with Truvada that are unfavourable?
https://www.drugs.com/interactions-check.php?drug_list=3500-0,971-1696
AHSCT is not a drug but a procedure.
Is this trial you are proposing a combination therapy study to address inflammation via HSCT and then smouldering via BTKi post HSCT? I am going to do HSCT shortly, perhaps tolebrutinib would be something to consider post HSCT? Or if your neurofilament testing is normal post HSCT there might be no need to take any BTKi's?
Yes, the AHSCT addresses any residual focal inflammation, as most subjects eligible for this trial with a PIRA event will have been on a high-efficacy DMT. The AHSCT is then followed by a CNS penetrant therapy targeting smouldering MS.
I am not sure AHSCT will be sufficient as a large number of patients with PIRA (progressive MS) who have AHSCT continue to get worse.
Do you mean HSCT for RRMS could be sufficient for long-term remission without ever encountering PIRA for life meaning no need for BTKi? Alternatively, people who have HSCT while they are at the PIRA stage are going to need a BTKi because HSCT is not likely to stop PIRA. Is that what you mean Prof G? So once you cross that PIRA rubicon there is no going back.
This study is only for patients with established smouldering MS, i.e. having documented PIRA.
Re: "Do you mean HSCT for RRMS could be sufficient for long-term remission without ever encountering PIRA for life meaning no need for BTKi?"
Yes, a minority of pwMS who are treated with AHSCT and alemtuzumab early in the course of their disease (<2 years after symptom onset) are in long-term remission (>15 years) with no signs of smouldering MS. They may even be cured of having MS.
This post and its responses makes me feel rather desperate. So many of these therapeutic proposals are guesses that probably are not going to provide clear results and will rase the question, lurking in the confusion, what is actually happening in the CNS tissues? What are the cellular and immune mechanisms that can account for the clinical events, including progression and smouldering?
I am now addressing myself; 'go to the tissues they will tell you what the answer is', and consequently what therapeutic opportunities that can cut through the enigma. The current therapeutic experiments cost very much more than laboratory investigations to answer the question, what is going on the CNS in MS?