What good is to be free of relapses and focal MRI activity if you are getting worse? It is not relapses and MRI activity that are important, but smouldering disease.
Thank you for your post Prof G & a Happy New Year to you & all. Here's to a better 2022 & I hope we can all get on top of this virus & start living again!
I look forward to your study with regards to dosing as it makes sense that you might need to give more of the medication, depending on weight/build. Do you feel there's difference too with male/female dosing?
The issue with smouldering MS is that some Neurologists do not talk or engage with this as a conversation with their patients. I've had smouldering MS almost since diagnosis (a few brief periods of it affecting me less) but majority of the time it has been there all the time. My mobility has gotten worse & I have times in the morning when I'm not sure my legs will work! I take a good slow supported few steps, then (I'm like an old wind up toy) get going, the more I walk the less difficulty. As soon as I sit I can feel my legs ceasing up again - & I have to start up all over again!. This varies throughout the day but becomes more severe around tea time! I have other symptoms, some minor but new, some there (again worsening) but I deal with throughout as a daily struggle. I know there is a lot going on in my body & the way I describe it is like my whole body is inflamed, with parts on fire, on & off throughout the day! The pain, spasticity , mobility along with urine urgency, tinnitus, tingling & numbness in head, neck & hands - all come and go throughout & the only time I can mentally cope with all this going on is when my mind is busy & I'm really distracted from it all. My MS team are all lovely & I have a good relationship with my Neuro but I would like to have tests to see what is happening (other than MRI) and to check for viruses, what level of antibodies have I made after having 3 vaccines, inflammation checks & reasons why this all seems to be getting worse, especially as I'm on a DMT Ocrelizumab. I have asked to have a f/f in January & I would like to know what the future might look like for me - Not only with MS but with covid management (all vaccines - best time and plan) & how is your mental health too. Do you think there is any further guidance for Neurologist to be more engaging with their patients about and to set an agenda to achieve a better and more encouraging appointment result. We patients can go armed with an agenda but we must feel the Neurologist is happy to engage at the outset & if this appointment doesn't achieve an agreeable outcome (say for instance time has ran out) to set another appointment there and then or give the patient your email address so that you can communicate with each other! Most patients would not abuse this trust & work on the basis of reasonable contact too! If the patient isn't sticking to the etiquette, then their address should deleted & back to appointments only!
There is a definite requirement for further research to set up tests for viruses, inflammation & new drugs to be made to treat the viruses (EBV) & better drugs for treating inflammation that can be taken on a regular basis, that aren't harmful to other organs or parts of your body. Treatments that are therapies but also make the pwMS feel better, less pain, more ability to move, less difficulties with mental health issues. The Unis are out there and work is being done, I know that through some recent research projects, I've been involved in - but we need to raise our profile again & keep on pushing. Thank you to all that do and make a difference :)
The Norfolk countryside looks lovely & stay well and safe everyone. God Bless xxx
Happy New Year! Another great article, Prof G. I was dxd in 1993, and had about 1 relapse a year for the first 4 or 5 years, with full or nearly full recovery. Have not had a technical "relapse" since, but my disability has steadily increased so I am at an EDSS of approximately 6.0-6.5. I have had MRIs every year like clockwork. Every time I get the written report it says "little to no interval change". But one can look at an MRI from 1995 and an MRI from 2021 and see a significant difference in the # and the size of the lesions and a huge amount of brain volume loss. I think in my case the atrophy is the driving force in my progression. Is there a direct relation between brain volume loss and functional reserve? I have been on ocrevus for 2.5 years and was thinking about switching to ofatumumab, but after reading this I'm not sure it will do any good. Maybe Lemtrada or HSCT would be the way to go. I know u can't give advice to individual patients, I just wanted to give my history. By the way, I think the term "smouldering MS" is BRILLIANT. It gives the reader a real visceral way to think of this bloody disease.
I had constant, severe relapses in the first 5 years post dx & there were no DMTs then. Fast forward to 2009 & I started Tysabri. Miraculous. Stopped all further relapses. Now about to start Ocrevus as tested very high JCV+.
I can't walk more than 800m, my bladder stopped working on dx. At 61, I look normal but am permanently disabled by early attacks. I presume I will now go downhill fast as Tysabri was preventing deterioration.
Even if add on treatments become available, the damaged myelin & dead axons/neurons can't be replaced. However, for the next generation, it's important to develop these new treatments and stop the smouldering. I hope someone is working on this now.
Happy New Year Prof Giovannoni. I hope you had a lovely Christmas break.
Thank you for your fantastic article. It is incredibly helpful to learn more about smouldering disease. I have explained this smouldering process to my brother (who also has MS) and he finds it valuable to know, too. His MRI scans have been stable for the last five years and yet his symptoms have worsened. Unfortunately his MS team haven't provided clarity as to why this might be the case; they tend to blame anything other than MS which is not at all applicable, as he is generally a healthy young man. Smouldering MS certainly makes sense. Thank you for your articles, they mean the world.
Take good care and I look forward to your next update.
This post is so interesting - thank you. I switched to Ocrelizumab in 2018 (from Tysabri) but since 2020 due to the pandemic have had my treatment less frequently - around every 9 months. Other than always feeling pretty ill for a few days post treatment I have had no relapses or obvious disease progression for several years. I have been given the option to switch to Ofatumumab which I was strongly considering. I am now thinking this could be a mistake in terms of preventing disease progression until more is known? Thanks again
I have several questions: 1) If an anti-viral agent is shown effective at some point, would you expect anti-viral treatment to be life long or only during B-cell repopulation. 2) Is it possible to look at certain DMT trial data for treatments that are highly immunosuppressive to see if concomitant anti-viral treatment (used to prevent things such as herpes/CMV/zoster) has any effect. 3) would you expect subcutaneously administered antibodies anti-cd20 to better penetrate tissue compartments (at least locally where problematic B-cells may reside). I wonder if the injection location of Kesimpta might have any effect (i.e upper arm injection to access cervical lymph nodes where EBV+ memory cells are likely to reside)
I'm especially interested to hear you value stories. I believe stories in many fields are under exploited (they play a massive rôle in reading acquisition as demonstrated by a very small Scottish research project about 30 years ago).
Stories are especially useful when used to raise morale in unhappy or sick people. I believe positive stories of hope could well help pwMS. I'm taking part in a really interesting research project called NEON (Nottingham University) to gather stories of recovery from mental illness, such as depression, which affects more pwMS that the gen pop. It might interest readers of the Selfie to access the stories online or possible get involved. It is a 5 year project which has a few more months to run.
Jan 2, 2022·edited Jan 2, 2022Liked by Gavin Giovannoni
HNY Prof. Giovannoni,
My question is:
I thought the monoclonal antibodies were not CNS penetrant. Why would more highly dosed ocrelizumab be more able to reach the CNS vs the lower dosed? Could you explain how this can be mechanistically possible?
Also, unrelated to this post: could we have your opinion on NAD+, NMN, metformin for MS?
Another fantastic and informative post. What really boggles me is why are so many MS specialist in denial about smouldering MS? As I've mentioned before, I really had to do battle to get my treatments switched as I knew I was progressing and my physios agreed, even my own consultant said that doctors must listen to what their patients say about their MS and that underlying progression in MS despite stable MRIs is something that can never be ruled out. I was eventually switched treatments to Ocrevus but not before I underwent plenty of phychological evaluations as an inpatient as one particular doctor fought to say I wasn't progressing and it was phychosomatic instead. Of course this couldn't be proven as I was living with MS which could explain my symptoms. But why do so many doctors fail to listen to their patients' experiences of the disease? The most common topic of discussion among my friends with MS is how they notice new symptoms in absence of MRI activity and how these new symptoms get dismissed. It's very worrying and adds stress on the patient who has to fight and beg to be heard. What must we do to help change this?
I remember the case you mentioned about switching from tysabri to an irt but thought that the patient had decided on HSCT. What changed? I also recall a case where you stated that you would try to encourage a patient on ocrelizumab to pursue lemtrada over HSCT and would spend time with them talking through the differences. But then in thus article you discuss the same mode of action. I am asking because as a leyman, the cns penetrant element of HSCT appears more appealing than lemtrada in arresting smouldering disease. A lot of HSCT vets talk of halting progression although that could be considered spin. Its very difficult to make an informed call in this scenario
I empathize with speaking the truth when it might not be taken well by all, and I empathize with those who may not want to hear it. I believe you hit the MS Dart Board, dead center, with this one. I can feel the vibrations 3500 miles away! Happy New Year and thank you.
HNY prof G! I have loads of Q’s, some of which probably my lack of understanding a lot of the mechanisms going on, so sorry if asking you something you’ve already covered, but…1) as Lemtrada depletes circulating B and T cells, is that a different kind of B cell depletion you talk about in the new trials? 2) when neurologists send the yearly report of ‘no change, no new lesions etc’ is brain atrophy visible to them and if so why are they not commenting on it? 3) even with NEIDA and no obvious increase in progression, is a pwMS still effectively experiencing the smouldering MS as a constant background disease no matter what? 4) does a pwMS always progress to secondary progressive in time, is it set by internal clock from onset and is that interval delayed by IRT or other factors and can it ever be delayed indefinitely or will it always just happen? 5) if there’s always smouldering underlying from the start, does that just mean we are all progressive at start but some have relapses/visible lesions as well for a period of time and then that subsides to leave what was always there?
So if we are NEDA, on regular 6 month dose of ocrevus, and have a low EDS score 2.5 what should we have our neurologist do to track smouldering disease? I have been reading about this for a while but it is somewhat overwhelming as it seems like there are no good measures? Or approaches to this issue for patients.
"I highlight this dilemma in a recent case study of someone on natalizumab who was NEIDA and clinically stable but had progressive brain volume loss and wanted to switch to alemtuzumab".
I wish this patients a lot of luck. She needs it now.
Now if this switch proves helpful in slowing down smouldering MS (big if), would that not show that Tysabri (surely out of patent by then) is actually playing a big role in slowing dow MS as we know that alemtuzumab only works in the first 5 years from onset for some treatment naive patients?
Thank you for your post Prof G & a Happy New Year to you & all. Here's to a better 2022 & I hope we can all get on top of this virus & start living again!
I look forward to your study with regards to dosing as it makes sense that you might need to give more of the medication, depending on weight/build. Do you feel there's difference too with male/female dosing?
The issue with smouldering MS is that some Neurologists do not talk or engage with this as a conversation with their patients. I've had smouldering MS almost since diagnosis (a few brief periods of it affecting me less) but majority of the time it has been there all the time. My mobility has gotten worse & I have times in the morning when I'm not sure my legs will work! I take a good slow supported few steps, then (I'm like an old wind up toy) get going, the more I walk the less difficulty. As soon as I sit I can feel my legs ceasing up again - & I have to start up all over again!. This varies throughout the day but becomes more severe around tea time! I have other symptoms, some minor but new, some there (again worsening) but I deal with throughout as a daily struggle. I know there is a lot going on in my body & the way I describe it is like my whole body is inflamed, with parts on fire, on & off throughout the day! The pain, spasticity , mobility along with urine urgency, tinnitus, tingling & numbness in head, neck & hands - all come and go throughout & the only time I can mentally cope with all this going on is when my mind is busy & I'm really distracted from it all. My MS team are all lovely & I have a good relationship with my Neuro but I would like to have tests to see what is happening (other than MRI) and to check for viruses, what level of antibodies have I made after having 3 vaccines, inflammation checks & reasons why this all seems to be getting worse, especially as I'm on a DMT Ocrelizumab. I have asked to have a f/f in January & I would like to know what the future might look like for me - Not only with MS but with covid management (all vaccines - best time and plan) & how is your mental health too. Do you think there is any further guidance for Neurologist to be more engaging with their patients about and to set an agenda to achieve a better and more encouraging appointment result. We patients can go armed with an agenda but we must feel the Neurologist is happy to engage at the outset & if this appointment doesn't achieve an agreeable outcome (say for instance time has ran out) to set another appointment there and then or give the patient your email address so that you can communicate with each other! Most patients would not abuse this trust & work on the basis of reasonable contact too! If the patient isn't sticking to the etiquette, then their address should deleted & back to appointments only!
There is a definite requirement for further research to set up tests for viruses, inflammation & new drugs to be made to treat the viruses (EBV) & better drugs for treating inflammation that can be taken on a regular basis, that aren't harmful to other organs or parts of your body. Treatments that are therapies but also make the pwMS feel better, less pain, more ability to move, less difficulties with mental health issues. The Unis are out there and work is being done, I know that through some recent research projects, I've been involved in - but we need to raise our profile again & keep on pushing. Thank you to all that do and make a difference :)
The Norfolk countryside looks lovely & stay well and safe everyone. God Bless xxx
Happy New Year! Another great article, Prof G. I was dxd in 1993, and had about 1 relapse a year for the first 4 or 5 years, with full or nearly full recovery. Have not had a technical "relapse" since, but my disability has steadily increased so I am at an EDSS of approximately 6.0-6.5. I have had MRIs every year like clockwork. Every time I get the written report it says "little to no interval change". But one can look at an MRI from 1995 and an MRI from 2021 and see a significant difference in the # and the size of the lesions and a huge amount of brain volume loss. I think in my case the atrophy is the driving force in my progression. Is there a direct relation between brain volume loss and functional reserve? I have been on ocrevus for 2.5 years and was thinking about switching to ofatumumab, but after reading this I'm not sure it will do any good. Maybe Lemtrada or HSCT would be the way to go. I know u can't give advice to individual patients, I just wanted to give my history. By the way, I think the term "smouldering MS" is BRILLIANT. It gives the reader a real visceral way to think of this bloody disease.
I had constant, severe relapses in the first 5 years post dx & there were no DMTs then. Fast forward to 2009 & I started Tysabri. Miraculous. Stopped all further relapses. Now about to start Ocrevus as tested very high JCV+.
I can't walk more than 800m, my bladder stopped working on dx. At 61, I look normal but am permanently disabled by early attacks. I presume I will now go downhill fast as Tysabri was preventing deterioration.
Even if add on treatments become available, the damaged myelin & dead axons/neurons can't be replaced. However, for the next generation, it's important to develop these new treatments and stop the smouldering. I hope someone is working on this now.
Happy New Year Prof Giovannoni. I hope you had a lovely Christmas break.
Thank you for your fantastic article. It is incredibly helpful to learn more about smouldering disease. I have explained this smouldering process to my brother (who also has MS) and he finds it valuable to know, too. His MRI scans have been stable for the last five years and yet his symptoms have worsened. Unfortunately his MS team haven't provided clarity as to why this might be the case; they tend to blame anything other than MS which is not at all applicable, as he is generally a healthy young man. Smouldering MS certainly makes sense. Thank you for your articles, they mean the world.
Take good care and I look forward to your next update.
Best wishes,
Jennifer
Is the Sizomus trial recruiting? How would I sign up? I'm close to London and under a London Consultant.
This post is so interesting - thank you. I switched to Ocrelizumab in 2018 (from Tysabri) but since 2020 due to the pandemic have had my treatment less frequently - around every 9 months. Other than always feeling pretty ill for a few days post treatment I have had no relapses or obvious disease progression for several years. I have been given the option to switch to Ofatumumab which I was strongly considering. I am now thinking this could be a mistake in terms of preventing disease progression until more is known? Thanks again
I am a 173 tall woman and I weigh 52 kg. My first Ocrelizumab infusion, two weeks ago, was 300mg and another 300mg yesterday.
The next in July (600 mg).
Can it be considered a high dose, therefore more effective?
What can be considered a management of Ocrelizumab as an IRT? How many doses, how many mg, how often and for how long?
Thank you!
I have several questions: 1) If an anti-viral agent is shown effective at some point, would you expect anti-viral treatment to be life long or only during B-cell repopulation. 2) Is it possible to look at certain DMT trial data for treatments that are highly immunosuppressive to see if concomitant anti-viral treatment (used to prevent things such as herpes/CMV/zoster) has any effect. 3) would you expect subcutaneously administered antibodies anti-cd20 to better penetrate tissue compartments (at least locally where problematic B-cells may reside). I wonder if the injection location of Kesimpta might have any effect (i.e upper arm injection to access cervical lymph nodes where EBV+ memory cells are likely to reside)
Happy new year Prof G.,
I'm especially interested to hear you value stories. I believe stories in many fields are under exploited (they play a massive rôle in reading acquisition as demonstrated by a very small Scottish research project about 30 years ago).
Stories are especially useful when used to raise morale in unhappy or sick people. I believe positive stories of hope could well help pwMS. I'm taking part in a really interesting research project called NEON (Nottingham University) to gather stories of recovery from mental illness, such as depression, which affects more pwMS that the gen pop. It might interest readers of the Selfie to access the stories online or possible get involved. It is a 5 year project which has a few more months to run.
HNY Prof. Giovannoni,
My question is:
I thought the monoclonal antibodies were not CNS penetrant. Why would more highly dosed ocrelizumab be more able to reach the CNS vs the lower dosed? Could you explain how this can be mechanistically possible?
Also, unrelated to this post: could we have your opinion on NAD+, NMN, metformin for MS?
Thank you beforehand for your reply
Another fantastic and informative post. What really boggles me is why are so many MS specialist in denial about smouldering MS? As I've mentioned before, I really had to do battle to get my treatments switched as I knew I was progressing and my physios agreed, even my own consultant said that doctors must listen to what their patients say about their MS and that underlying progression in MS despite stable MRIs is something that can never be ruled out. I was eventually switched treatments to Ocrevus but not before I underwent plenty of phychological evaluations as an inpatient as one particular doctor fought to say I wasn't progressing and it was phychosomatic instead. Of course this couldn't be proven as I was living with MS which could explain my symptoms. But why do so many doctors fail to listen to their patients' experiences of the disease? The most common topic of discussion among my friends with MS is how they notice new symptoms in absence of MRI activity and how these new symptoms get dismissed. It's very worrying and adds stress on the patient who has to fight and beg to be heard. What must we do to help change this?
I remember the case you mentioned about switching from tysabri to an irt but thought that the patient had decided on HSCT. What changed? I also recall a case where you stated that you would try to encourage a patient on ocrelizumab to pursue lemtrada over HSCT and would spend time with them talking through the differences. But then in thus article you discuss the same mode of action. I am asking because as a leyman, the cns penetrant element of HSCT appears more appealing than lemtrada in arresting smouldering disease. A lot of HSCT vets talk of halting progression although that could be considered spin. Its very difficult to make an informed call in this scenario
I empathize with speaking the truth when it might not be taken well by all, and I empathize with those who may not want to hear it. I believe you hit the MS Dart Board, dead center, with this one. I can feel the vibrations 3500 miles away! Happy New Year and thank you.
HNY prof G! I have loads of Q’s, some of which probably my lack of understanding a lot of the mechanisms going on, so sorry if asking you something you’ve already covered, but…1) as Lemtrada depletes circulating B and T cells, is that a different kind of B cell depletion you talk about in the new trials? 2) when neurologists send the yearly report of ‘no change, no new lesions etc’ is brain atrophy visible to them and if so why are they not commenting on it? 3) even with NEIDA and no obvious increase in progression, is a pwMS still effectively experiencing the smouldering MS as a constant background disease no matter what? 4) does a pwMS always progress to secondary progressive in time, is it set by internal clock from onset and is that interval delayed by IRT or other factors and can it ever be delayed indefinitely or will it always just happen? 5) if there’s always smouldering underlying from the start, does that just mean we are all progressive at start but some have relapses/visible lesions as well for a period of time and then that subsides to leave what was always there?
Thanks and sorry for the essay!
So if we are NEDA, on regular 6 month dose of ocrevus, and have a low EDS score 2.5 what should we have our neurologist do to track smouldering disease? I have been reading about this for a while but it is somewhat overwhelming as it seems like there are no good measures? Or approaches to this issue for patients.
"I highlight this dilemma in a recent case study of someone on natalizumab who was NEIDA and clinically stable but had progressive brain volume loss and wanted to switch to alemtuzumab".
I wish this patients a lot of luck. She needs it now.
Now if this switch proves helpful in slowing down smouldering MS (big if), would that not show that Tysabri (surely out of patent by then) is actually playing a big role in slowing dow MS as we know that alemtuzumab only works in the first 5 years from onset for some treatment naive patients?