New data shows that natalizumab has an impact on chronic active lesions, including slowly expanding lesions, and indicates that natalizumab is a potentially effective treatment for smouldering MS.
Unfortunately, I sometimes have to use the term SPMS, which I hate. As you are aware MS is one disease. The decision on what DMT to go onto requires a lot of information, which is why I can't recommend anything specific. This newsletter and podcast is making the point that even if you have more advanced MS it is still modifiable.
I am encouraged. For personal reasons I need to find how modifiable my condition is.
What do I need to do to get a second opinion on my treatment options? I’ve tried to email you directly. Should I request my GP or neurologist to request an opinion from you or your clinic? Thanks Mary-Ann
I, sadly, will never get tired of hearing about ‘the real MS’ or 'smouldering MS' because I expect to have it till I die. I will always resist my diagnosis being changed from relapsing/remitting MS to secondary progressive MS because of the implications it has on treatment, or rather lack of treatment. It horrifies me when people say I should be glad when MRI scans show lack of activity. I was incredibly relieved when I had more activity, so I could have Lemtrada and get off Tecfidera. If they invent a treatment in my lifetime that reverses damage done by MS, or cures it, I want access to that.
Agree! Rrms and active MS are the key. I regret listening to physicians at one of the most influential medical centers here (states). Four years ago, I was advised I had burned out, plateaued and I’d be fine. Go off interferon beta 1-a after 20 years! I continued relapses - and I have lately plummeted, particularly eyesight, vertigo, balance, sleeping. I’m now using a rollater, interchanged with a stick and I’m quite sedentary. I wish I’d have known all of this, and now I’m old! (Sad face…) I’m glad I asked for guidance on here re what dmd is safe at this point at my age. (Thanks Prof G) Will see the new neurologist who does agree the disease progresses, even with neid. We’ll see…
Sadly, recrudescence of MS disease activity after stopping DMTs is very unpredictable. I have many patients who have done this and paid a high price. It needs to be done carefully.
I had no idea. It has only now in the last year begun to steamroll, mainly brain function, balance, nystagmus. I will see the neurologist on Thursday who had suggested a mod (very glad I checked with you). I will see if she recommends a less suppressing dmd. Here’s hoping!
I am totally shocked that on England pwMS are taken off their DMT when they are assessed to have progressed to SPMS. That’s absolutely appalling! Even if you are not able to ambulate as well you still have lots of neurological functions you want to keep!!! That seems like a punishment for people who are unlucky enough to have progressed. It is disability discrimination writ large!!
Now that siponimod is licensed for active SPMS and NHS England have capitulated and said that people who are getting worse, despite being NEIDA on a DMT and are labelled as SPMS can be switched to siponimod I suspect fewer and fewer patients with SPMS will not be treated. The latter however does not cover people who need a wheelchair.
Well that’s a small step in the right direction but I am still shocked that if you are in a wheelchair you are literally dismissed as not being worthy of treatment. I look up to the NHS (I grew up in London now living in New Zealand) and I am so disappointed that pwSPMS are treated in this way. Thank you for advocating for pwMS it is very much appreciated.
I can’t take this due to very high GGT results and stomach problems. 4 years on Fingolimod. I’m told Siponimod is likely to cause same problem. I’m not offered anything else. A part from a rushed 10 minute yearly review
I have been receiving natalizumab sinc 2017. I was diagnosed in 2000.i am ambulatory and my progression is hardly measurable. The senior neurologist gave me 4 MRIs last year. I am NEDA. atrophy was my big fear as i seemed to be becoming more confused. At the end of the year i lost my husband and he had been my carer. I think that in hindsight, this was a mistake, (for him to assume responsibility). I am managing quite well now on Fampyra and sativex and betmiga. I rsponded very well to fampyra. I even managed to jog! My neurologist at that time was overjoyed. I still forget things and fall from time to time. But as my case is treated as a compassionate reaction, i still receive blessed tysabri. I am jc negative. I started natalizumab jc positive but with a very low viral load and after a year, i was negative again and have remained that way. I use a stick to help with balance.
MS spasticity pulled my body apart with great pain and i had to have 2 knee replacements as the tracking that my ,ligaments relied on was badly aligned.
Thankyou for these thoughts. I have taken great comfort from them.
“ It has never made sense to me not to be able to prescribe a DMT to pwMS simply because they needed a wheelchair as a result of a devastating spinal cord relapse.”
And yet you still follow the objectively evil and non-scientific NHS guidelines…? What exactly are you worried is going to happen to you? Having some kind of letter of reprimand put in your file? An NHS trust was recently exposed as literally letting babies die in order to keep their Caesarean section rates down and no-one suffered any consequences. The only thing the regulators ever did is send them letters. Is it worth being frightened of these non-existent bureaucratic repercussions? If a scandal ever did start it would be incredibly easy to get the public on your side through the media. Please stop following evil orders from an evil bureaucracy.
Now I feel stupid stopping ocrelizumab after 2 years with low NFL and a tiny bit of atrophy at the cervical level on MRI. I did this because I progressed from EDSS 4 tot 6. I lost strength In my left leg and also my left hand. This damage was probably already in the "pipe line" Sure hope I am not getting placebo in the Perseus trial which I will be starting 13th of July. Hope BTK is worth it cause this seems like a risk
BTK will definitely not be better than Lemtrada or HSCT. And you have a 50% chance of getting placebo… Please do what is best for yourself and don’t participate in any clinical trial where the comparator isn’t a high efficacy DMT.
I suspect not for fingolimod based on the negative PPMS study that showed no impact on brain volume loss. The story for siponimod and possibly the other new generation MODs is different. They appear to have a greater impact on CNS pathology.
Dear Prof G, you will read on the 'Why is natalizumab not licensed to treat progressive MS?' thread, Mark Freedman's time (potentially yours too?) has been used inefficiently. A little more basic info in the 'about' section may stop this?
Chris, this platform is not ideal for this and is why blogging platforms are not ideal for curated information. This is why I am in the process of working on a curated, indexed MS-Selfie microsite to provide basic information in an easy to find format. Hopefully the site will be ready for a soft launch by the end of the summer.
Ps sorry also meant to say I listen to vlogs sometimes if a subject I particularly want to understand. Would have listened to this one but am on a train and don't like earphones
Could natalizumab’s impact on peripheral blood NFL levels and chronic active lesions, including SELs, allow a reversal of the neurodegenerative pathology and allow some neuroregeneration and recovery of function?
Idea that axons might sprout and new synapses form is beyond exciting :)
Was the ASCEND population that much more disabled than that in EXPAND siponimod (more than 50% needing a stick)? EXPAND primary outcome also time to confirmed progression - same as ASCEND?
Yes, the ASCEND population was the most advanced in terms of median EDSS, proportion of subjects at >=6.0 and the proportion classified as inactive at baseline (no recent relapses and/or Gd-enhancing lesions). What this data is telling us is that we need very high-efficacy DMTs to manage MS even in the more advanced stages.
Being a young person with SPMS with advanced disability, I'm really concerned if I would be able to get my lost functions back. Professor how far do you see restorative therapies showing up in the market from now?
As someone on Tysabri with constant anxiety about PML (I'm JC negative) why don't we have at this point either treatment for it or a vaccine for JC virus?
A vaccine would of course only help those negative but that's still a significant chunk of people
Found it unusual that biogen hasn't invested in getting a fix as it's their money maker product.
Vaccines and antivirals for a new class of virus takes time and investment. What people don't realise that the COVID-19 vaccines may have been tested and licensed in less than 12 months, but the were an extension of research work that went back 20+ years. The work on human polyomaviruses (formerly known as papovaviruses), which the JCV belongs to, is not that as advanced. However, with the mRNA platforms some of the new vaccine companies may change their minds.
Is there anything on the horizon for PML treatment? A JC vaccine would be great for the % of population who are negative but even treatment would be amazing
Are there any known ways to avoid JC virus? I'm still negative but no clue what I should or shouldn't be doing
Re: horizon for PML treatment: only immunotherapy in the immunosuppressed. The latter is not a problem in pwMS on natalizumab as their immune systems are intact and able to fight the virus.
When you stop natalizumab the immune system traffics back into the nervous system finds the virus and clears it. In people who have a heavily suppressed immune system they need to have their immune systems stimulated to fight the virus. The mortality of PML in pwMS is now less than 10%, but in the immunosuppressed it is over 80%.
PML is pwMS on natalizumab is very different to PML in the systemically immunosuppressed.
That is really good info. To be honest I had no clue about that and always assumed being JC positive then getting PML = death sentence. Hence why staying on Tysabri I didn't want to go for more than 12 months.
As someone who isn't immune suppressed and not been on any other DMT prior to Tysabri that gives me a lot of relief.
My neuro constantly assured me of the low risk but it's always in the back of my mind. Thank you
Your point about a delayed effect on EDSS cannot be overstated. Stopping inflammation today does not stop the processes underlying progression that started well before the start of anti-inflammatory treatment. We saw this in our HSCT patients. Improvements are similar delayed. However, the PML risk cannot be understated. Interval dosing was NOT used in ASCEND and is possibly still effective in RRMS but not proven. SPMS patients are typically older and therefore at greater risk of PML. Treating beyond 24 months greatly increases the risk and you are advocating for a 3+ year treatment. I am not sure that the theoretical benefits outweigh the very real risks.
What’s the risk of suicide due to loss of neurological function and independence from brain and spinal cord damage…? And what gives you the right to decide how much brain damage is acceptable for other people to accrue? I do not believe for one second that if you were diagnosed with “progressive” MS and started experiencing loss of neurological function for yourself that you would choose not to be treated in order to avoid risk of PML.
The risk of severe morbidity (QoL which people rate worse than death) from untreated MS is essentially 100%, whereas the risk of PML is incredibly tiny, and even tinier with modern risk reduction strategies. How many bedbound people with end-stage MS have you ever seen? How often do you set foot in the care homes where these people live? This is a far, far more likely fate for MS patients than death or morbidity from PML.
The risk with Tysabri is significant and the benefit is questionable. It will not rescue the folks you describe. And yes, I see plenty of the people you describe. You can do as you wish, I am simply commenting. Is that not allowed? Believe what you want. This is the benefit of a blog like this - to present points of view.
I don’t suggest it will rescue anyone, I suggest it should be used aggressively to prevent as many people as possible from getting to that state in the first place. Cancer treatments often carry significant side effects and their own mortality risks, and the benefit is often only a few extra years of survival, yet oncologists treat cancer aggressively nonetheless. Why would neurologists not do the same? Extra years free of disability progression is huge for MS patients and worth the risks of Tysabri. Be cautious about claiming otherwise without having experienced loss of neurological function for yourself.
I don't think I need to suffer from disease to appreciate the devastation it can create. I devoted my life to finding effective treatments and the goal is exactly the same as what you state, prevent the progression. There are better and more effective treatments without those risks.
True no PML risk but the infection risks are there as are fatalities
And HSCT doesn't 100% work. It's very disingenuous to say that. It's not a cure at all so I don't think you can say nothing else needs to be taken post the treatment
If that was the case we would all get it if it 100% stopped ms. It doesn't - for a majority yes but my understanding it's anywhere from 60-75% effective the earlier you go for the procedure.
Which you could say lemtrada is similar in its long term efficacy
I wish it was 100%. It isn't. Happy to be proved wrong if it is however
Clearly you need a better understanding of the treatment. Not all are the same. But no point discussing further as you seem quite fixated on your ideas.
My understanding is there isn't a single treatment including HSCT that can 100% stop MS. I have seen people who did HSCT have to go onto a DMT same with lemtrada
Anyway not trying to argue just using the data I have read. If you have a study that shows HSCT stops MS for all patients I'd love to read it.
Our Canadian experience is that 100% have not needed any further treatment and nobody in 20+ years has had a single attack or new MRI lesion. But we believe in "go big or go home". Don't believe all that you hear/read on social media.
Re PML risk; I agree it is not insignificant, but who is taking the risk? I think this study shows us that anti-inflammatory therapies work in SPMS and that inflammation driven by peripheral immune mechanisms is still driving some of the smouldering pathology.
I feel my being categorised as SPMS is allowing the neurological community to write me off “.
What would you recommend: AHSCT or medication like cladribine or other DMTS ? Mary-Ann
Unfortunately, I sometimes have to use the term SPMS, which I hate. As you are aware MS is one disease. The decision on what DMT to go onto requires a lot of information, which is why I can't recommend anything specific. This newsletter and podcast is making the point that even if you have more advanced MS it is still modifiable.
I am encouraged. For personal reasons I need to find how modifiable my condition is.
What do I need to do to get a second opinion on my treatment options? I’ve tried to email you directly. Should I request my GP or neurologist to request an opinion from you or your clinic? Thanks Mary-Ann
I think you should start with a frank discussion with your own neurologist and see what they say.
I, sadly, will never get tired of hearing about ‘the real MS’ or 'smouldering MS' because I expect to have it till I die. I will always resist my diagnosis being changed from relapsing/remitting MS to secondary progressive MS because of the implications it has on treatment, or rather lack of treatment. It horrifies me when people say I should be glad when MRI scans show lack of activity. I was incredibly relieved when I had more activity, so I could have Lemtrada and get off Tecfidera. If they invent a treatment in my lifetime that reverses damage done by MS, or cures it, I want access to that.
Agree! Rrms and active MS are the key. I regret listening to physicians at one of the most influential medical centers here (states). Four years ago, I was advised I had burned out, plateaued and I’d be fine. Go off interferon beta 1-a after 20 years! I continued relapses - and I have lately plummeted, particularly eyesight, vertigo, balance, sleeping. I’m now using a rollater, interchanged with a stick and I’m quite sedentary. I wish I’d have known all of this, and now I’m old! (Sad face…) I’m glad I asked for guidance on here re what dmd is safe at this point at my age. (Thanks Prof G) Will see the new neurologist who does agree the disease progresses, even with neid. We’ll see…
Sadly, recrudescence of MS disease activity after stopping DMTs is very unpredictable. I have many patients who have done this and paid a high price. It needs to be done carefully.
I had no idea. It has only now in the last year begun to steamroll, mainly brain function, balance, nystagmus. I will see the neurologist on Thursday who had suggested a mod (very glad I checked with you). I will see if she recommends a less suppressing dmd. Here’s hoping!
I am totally shocked that on England pwMS are taken off their DMT when they are assessed to have progressed to SPMS. That’s absolutely appalling! Even if you are not able to ambulate as well you still have lots of neurological functions you want to keep!!! That seems like a punishment for people who are unlucky enough to have progressed. It is disability discrimination writ large!!
Now that siponimod is licensed for active SPMS and NHS England have capitulated and said that people who are getting worse, despite being NEIDA on a DMT and are labelled as SPMS can be switched to siponimod I suspect fewer and fewer patients with SPMS will not be treated. The latter however does not cover people who need a wheelchair.
Well that’s a small step in the right direction but I am still shocked that if you are in a wheelchair you are literally dismissed as not being worthy of treatment. I look up to the NHS (I grew up in London now living in New Zealand) and I am so disappointed that pwSPMS are treated in this way. Thank you for advocating for pwMS it is very much appreciated.
I can’t take this due to very high GGT results and stomach problems. 4 years on Fingolimod. I’m told Siponimod is likely to cause same problem. I’m not offered anything else. A part from a rushed 10 minute yearly review
I have been receiving natalizumab sinc 2017. I was diagnosed in 2000.i am ambulatory and my progression is hardly measurable. The senior neurologist gave me 4 MRIs last year. I am NEDA. atrophy was my big fear as i seemed to be becoming more confused. At the end of the year i lost my husband and he had been my carer. I think that in hindsight, this was a mistake, (for him to assume responsibility). I am managing quite well now on Fampyra and sativex and betmiga. I rsponded very well to fampyra. I even managed to jog! My neurologist at that time was overjoyed. I still forget things and fall from time to time. But as my case is treated as a compassionate reaction, i still receive blessed tysabri. I am jc negative. I started natalizumab jc positive but with a very low viral load and after a year, i was negative again and have remained that way. I use a stick to help with balance.
MS spasticity pulled my body apart with great pain and i had to have 2 knee replacements as the tracking that my ,ligaments relied on was badly aligned.
Thankyou for these thoughts. I have taken great comfort from them.
“ It has never made sense to me not to be able to prescribe a DMT to pwMS simply because they needed a wheelchair as a result of a devastating spinal cord relapse.”
And yet you still follow the objectively evil and non-scientific NHS guidelines…? What exactly are you worried is going to happen to you? Having some kind of letter of reprimand put in your file? An NHS trust was recently exposed as literally letting babies die in order to keep their Caesarean section rates down and no-one suffered any consequences. The only thing the regulators ever did is send them letters. Is it worth being frightened of these non-existent bureaucratic repercussions? If a scandal ever did start it would be incredibly easy to get the public on your side through the media. Please stop following evil orders from an evil bureaucracy.
Now I feel stupid stopping ocrelizumab after 2 years with low NFL and a tiny bit of atrophy at the cervical level on MRI. I did this because I progressed from EDSS 4 tot 6. I lost strength In my left leg and also my left hand. This damage was probably already in the "pipe line" Sure hope I am not getting placebo in the Perseus trial which I will be starting 13th of July. Hope BTK is worth it cause this seems like a risk
BTK will definitely not be better than Lemtrada or HSCT. And you have a 50% chance of getting placebo… Please do what is best for yourself and don’t participate in any clinical trial where the comparator isn’t a high efficacy DMT.
Is fingolimod (and other mods) also effective against smouldering MS, as it prevents entry of lymphocytes into the CNS - but without the risk of PML?
I suspect not for fingolimod based on the negative PPMS study that showed no impact on brain volume loss. The story for siponimod and possibly the other new generation MODs is different. They appear to have a greater impact on CNS pathology.
Dear Prof G, you will read on the 'Why is natalizumab not licensed to treat progressive MS?' thread, Mark Freedman's time (potentially yours too?) has been used inefficiently. A little more basic info in the 'about' section may stop this?
Chris, this platform is not ideal for this and is why blogging platforms are not ideal for curated information. This is why I am in the process of working on a curated, indexed MS-Selfie microsite to provide basic information in an easy to find format. Hopefully the site will be ready for a soft launch by the end of the summer.
Ps sorry also meant to say I listen to vlogs sometimes if a subject I particularly want to understand. Would have listened to this one but am on a train and don't like earphones
Re
Could natalizumab’s impact on peripheral blood NFL levels and chronic active lesions, including SELs, allow a reversal of the neurodegenerative pathology and allow some neuroregeneration and recovery of function?
Idea that axons might sprout and new synapses form is beyond exciting :)
Was the ASCEND population that much more disabled than that in EXPAND siponimod (more than 50% needing a stick)? EXPAND primary outcome also time to confirmed progression - same as ASCEND?
Yes, the ASCEND population was the most advanced in terms of median EDSS, proportion of subjects at >=6.0 and the proportion classified as inactive at baseline (no recent relapses and/or Gd-enhancing lesions). What this data is telling us is that we need very high-efficacy DMTs to manage MS even in the more advanced stages.
Being a young person with SPMS with advanced disability, I'm really concerned if I would be able to get my lost functions back. Professor how far do you see restorative therapies showing up in the market from now?
Sadly., restorative therapies are some way off. But the best restorative therapy is exercise and rehabilitation. I assume you do both?
As someone on Tysabri with constant anxiety about PML (I'm JC negative) why don't we have at this point either treatment for it or a vaccine for JC virus?
A vaccine would of course only help those negative but that's still a significant chunk of people
Found it unusual that biogen hasn't invested in getting a fix as it's their money maker product.
Vaccines and antivirals for a new class of virus takes time and investment. What people don't realise that the COVID-19 vaccines may have been tested and licensed in less than 12 months, but the were an extension of research work that went back 20+ years. The work on human polyomaviruses (formerly known as papovaviruses), which the JCV belongs to, is not that as advanced. However, with the mRNA platforms some of the new vaccine companies may change their minds.
Is there anything on the horizon for PML treatment? A JC vaccine would be great for the % of population who are negative but even treatment would be amazing
Are there any known ways to avoid JC virus? I'm still negative but no clue what I should or shouldn't be doing
Re: horizon for PML treatment: only immunotherapy in the immunosuppressed. The latter is not a problem in pwMS on natalizumab as their immune systems are intact and able to fight the virus.
Isn't that the problem with people on natalizumab and PML that they (we) can't fight the virus which causes PML due to being positive and on Tysabri?
Sorry a bit confused there.
When you stop natalizumab the immune system traffics back into the nervous system finds the virus and clears it. In people who have a heavily suppressed immune system they need to have their immune systems stimulated to fight the virus. The mortality of PML in pwMS is now less than 10%, but in the immunosuppressed it is over 80%.
PML is pwMS on natalizumab is very different to PML in the systemically immunosuppressed.
That is really good info. To be honest I had no clue about that and always assumed being JC positive then getting PML = death sentence. Hence why staying on Tysabri I didn't want to go for more than 12 months.
As someone who isn't immune suppressed and not been on any other DMT prior to Tysabri that gives me a lot of relief.
My neuro constantly assured me of the low risk but it's always in the back of my mind. Thank you
Re avoiding: the JC virus is transmitted in saliva and urine. However, as it is ubiquitous it is difficult to avoid.
Well thankfully the only urine in my life is from my 2 year old haha
Your point about a delayed effect on EDSS cannot be overstated. Stopping inflammation today does not stop the processes underlying progression that started well before the start of anti-inflammatory treatment. We saw this in our HSCT patients. Improvements are similar delayed. However, the PML risk cannot be understated. Interval dosing was NOT used in ASCEND and is possibly still effective in RRMS but not proven. SPMS patients are typically older and therefore at greater risk of PML. Treating beyond 24 months greatly increases the risk and you are advocating for a 3+ year treatment. I am not sure that the theoretical benefits outweigh the very real risks.
“the very real risks.”
What’s the risk of suicide due to loss of neurological function and independence from brain and spinal cord damage…? And what gives you the right to decide how much brain damage is acceptable for other people to accrue? I do not believe for one second that if you were diagnosed with “progressive” MS and started experiencing loss of neurological function for yourself that you would choose not to be treated in order to avoid risk of PML.
Guess you have never seen anyone with PML. Severe morbidity or death in 75%. Makes MS look like a cake-walk. But, these are individual choices.
The risk of severe morbidity (QoL which people rate worse than death) from untreated MS is essentially 100%, whereas the risk of PML is incredibly tiny, and even tinier with modern risk reduction strategies. How many bedbound people with end-stage MS have you ever seen? How often do you set foot in the care homes where these people live? This is a far, far more likely fate for MS patients than death or morbidity from PML.
The risk with Tysabri is significant and the benefit is questionable. It will not rescue the folks you describe. And yes, I see plenty of the people you describe. You can do as you wish, I am simply commenting. Is that not allowed? Believe what you want. This is the benefit of a blog like this - to present points of view.
I don’t suggest it will rescue anyone, I suggest it should be used aggressively to prevent as many people as possible from getting to that state in the first place. Cancer treatments often carry significant side effects and their own mortality risks, and the benefit is often only a few extra years of survival, yet oncologists treat cancer aggressively nonetheless. Why would neurologists not do the same? Extra years free of disability progression is huge for MS patients and worth the risks of Tysabri. Be cautious about claiming otherwise without having experienced loss of neurological function for yourself.
I don't think I need to suffer from disease to appreciate the devastation it can create. I devoted my life to finding effective treatments and the goal is exactly the same as what you state, prevent the progression. There are better and more effective treatments without those risks.
There are risks with HSCT also. Significant ones - why pick up on Tysabri risk but not disclose the risk for HSCT?
Because after 1 HSCT nothing else needs to be taken. There is no PML. There are significant risks, but there are proven, not hypothetical, benefits.
True no PML risk but the infection risks are there as are fatalities
And HSCT doesn't 100% work. It's very disingenuous to say that. It's not a cure at all so I don't think you can say nothing else needs to be taken post the treatment
If that was the case we would all get it if it 100% stopped ms. It doesn't - for a majority yes but my understanding it's anywhere from 60-75% effective the earlier you go for the procedure.
Which you could say lemtrada is similar in its long term efficacy
I wish it was 100%. It isn't. Happy to be proved wrong if it is however
Clearly you need a better understanding of the treatment. Not all are the same. But no point discussing further as you seem quite fixated on your ideas.
I don't think I said anything incorrect?
My understanding is there isn't a single treatment including HSCT that can 100% stop MS. I have seen people who did HSCT have to go onto a DMT same with lemtrada
Anyway not trying to argue just using the data I have read. If you have a study that shows HSCT stops MS for all patients I'd love to read it.
Our Canadian experience is that 100% have not needed any further treatment and nobody in 20+ years has had a single attack or new MRI lesion. But we believe in "go big or go home". Don't believe all that you hear/read on social media.
Hi Mark,
Re PML risk; I agree it is not insignificant, but who is taking the risk? I think this study shows us that anti-inflammatory therapies work in SPMS and that inflammation driven by peripheral immune mechanisms is still driving some of the smouldering pathology.
I think we have always known there is "some" effect in "some" people ever since the interferon trials of yesteryear.