Big data confirms smouldering MS is the dominant driver of disability worsening in MS and that age and loss of reserve is a major factor in predicting recovery of function. Is there anything new here?
"The more people understand what is happening to their brains and spinal cords despite being on a DMT the better".
Like another commentator below, I have mixed feelings about this - for our mental health, is it really best to be fully informed, and know everything possible about the condition? The truth is, taking this approach (which I have done) can make me feel very bleak about the future... like I'm living with the sword of Damocles over my head.
It can take away the pleasure of my today.
I'm 37, and already had a lot of silent lesions by the point of diagnosis (in 2020), so I've missed the 'early intervention' route and then some. I'm now on ocrelizumab and currently 'fine' on the surface, but I've read enough about MS to know it's likely to hit me like a ton of bricks in the future. Sometimes I wonder if I'd have been better off not reading anything at all... (other days, of course, I'm glad I am informed because it means I feel better able to chase every marginal gain*).
I imagine most pwMS try as best as we can to make healthy choices, so to feel like we are somehow in control of our destinies -- but it is hard sometimes, to suppress the feeling that long-term, you're screwed anyway.
It's a tricky one.
*except a HSCT... my bank balance currently won't allow for that!
I know what you mean. I suspect it the same realisation most people have when they realise they are old and getting older. I am of the opinion that ageing is a disease that can be modified.
Choosing not to know is as important as choosing to find out. It is all about personal, but informed, choice.
I think for myself I would rather know. If I have choices to make and options then I can do something different. Either way I will fight like hell. I won't give up. This disease has taken so much from me now, i refuse to give up willingly what little i have left.
"The more people who understand what is happening to their brains and spinal cords despite being on a DMT the better". Not sure about this one to be honest. Considering that the evolution of treatments to tackle smouldering MS may take 10 years, of what benefit is this knowledge to the patient when they cant do a great deal about it? I understand why it would be better to have wider acceptance amongst the MS community, to push for quicker treatment, to build momentum on the development of drugs etc. I was sat in a room yesterday with one of the leading proponents of HSCT in the UK but the message of watch and wait was essentially still being rolled out. However for the patients with their hands tied and their brain being shredded....its pretty sh*t
Yes and no. Can you tell me why so many pwMS still smoke, don't exercise, eat unhealthily, don't practice intermittent fasting, have poor sleep hygiene, take anti-cholinergics, drink too much, etc. Treating smouldering MS is about so much more than just DMTs and pharmaceuticals.
Point taken, but its works both ways. The informed patient does all these things but MS and the destruction it is causing is always at the front of their mind. There is a balance i suppose, between not making every decision in the context of your disease and giving yourself the best chance.
I am more confused now than i was to start with.. for a couple of reasons.. Paroxetine is an SSRI.. I thought.. isnt it? I have been taking this anti depressant on and off cycling thru with a couple of others since I was in my early 30's. I have MDD.. So are SSRI not good either? or is only the Tricyclic antidepressants? SNRI make me nuts so i avoid them and take the SSRIs alone. I actually started having seizures on a combination drug. I am confused but thats not uncommon for me either
Not sure. It is not recommended, but this recommendation is not evidence based. From an evolutionary perspective I doubt it would be a problem. I have several Muslim patients who have done it during Ramadan and I am aware that it is used by some diabetologists to treat gestational diabetes. Some women, with severe hyperemsis gravidarum, do it any way. I am suspect that not using IF for pregnancy is unlikely to have a major impact on MS.
Feb 3, 2022·edited Feb 3, 2022Liked by Gavin Giovannoni
Thank you for sharing this important article. I have a question: I noticed that in the data sets most DMTs are included but not any IRTs. Do you think that PIRA could be less prevalent amongst IRT patients than with the rest of the treatments? Are there any data on the effect of IRTs on PIRA? Thank you beforehand for your reply.
Thanks for pointing this out! Yes, there is data out there that IRTs, in particular alemtuzumab and AHSCT, when used early in the course of MS seem to have a greater impact on smouldering MS than other DMTs. I suspect the same will hold for cladribine when used early; this is based on the ORACLE or CIS brain volume data and not the CLARITY or RRMS data.
I have always hypothesised that there is something fundamentally different between the mode of action of IRTs and maintenance therapies. We need to find out what this is.
It depends on what cohort you choose, the age of treatment and the length of follow-up. The alemtuzumab cohorts that have reported indicate that up to 20% have SPMS at 8 years of follow-up.
Please see: Brown et al. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA. 2019 Jan 15;321(2):175-187. doi: 10.1001/jama.2018.20588.
HSCT data is less clear. However, at 10 years only 55% of the relapsing-remitting cohort are free of progression and by inference the other 45% have SPMS. Please note this cohort will have more advanced disease with more damage before treatment hence the worse outcome compared to alemtuzumab.
Please see: Muraro et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017 Apr 1;74(4):459-469. doi: 10.1001/jamaneurol.2016.5867. PMID: 28241268; PMCID: PMC5744858
Top man, thanks Prof. I know there is no corresponding studies on anti CD20 but it's effectiveness at controlling MRI activity will surely make it difficult to pin point where RRMS ends and SPMS begins
Unfortunately there is no identifiable transition between RRMS and SPMS, they coexist and overlap with each to a greater or lesser extent. This is one of the main messages of the smouldering MS concept that #MS_is_1_not_2_or_3 diseases.
Feb 3, 2022·edited Feb 3, 2022Liked by Gavin Giovannoni
"DMTs only delayed the time from EDSS 1 to 4 (walking problems) by ~3.5 years and time to EDSS 6.0 or a walking stick by ~3.1 years."
Are some DMT's more effective than others at tackling Smouldering MS? Where does Tysabri fit in with effectiveness against smouldering MS? It's consistently said to be one of the most highly effective DMT's but that seems to be mostly just keeping relapses at bay which might not be that effective long term.
as I read that I was thinking about my experience, or I should say nightmare, with Mayzent (siponimod). It was absolute hell, honestly. I took it for 15 months and suffered for 14 of them.. Bad side effects. But really, I had no idea these DMTs only delay disability for that short time. I mean, you have to ask yourself.. Is it it all really worth it?
Feb 3, 2022·edited Feb 3, 2022Liked by Gavin Giovannoni
Super interesting and forwarded this to my MS Nurses in a vain attempt to encourage a conversation with my Neurologist about this later in the month. With the lack of symptoms and an annual MRI, I am a bit lost as what is to be done for my treatment of RRMS. I do not take any DMTs.
I look after my diet with the Overcoming MS wellness program, 20k+ steps daily and yoga 6 times a week and meditation. What more can I do?
That is very interesting given my experience ..I doubt like you I would have been given any DMTs either had they been available then. No further relapses etc…I just felt totally normal again …but initial two episodes meant total paralysis from waist down …
I think I have smouldering MS and it’s the elephant in the room at my neurology appointments.
3+ years post cladribine. Relapsed between Cladribine doses then did well.
However in last 12 months I have had many worstening symptoms incl my mobility. Two bad falls resulting in concussion. Many other debilitating symptoms BUT my MRI in May was stable. My neuro says I’m not eligible for DMTs so I’m getting worse and not able to get treatment. Feel left in no mans land. I have to wait for a relapse to be eligible for more treatment. Meanwhile I’m smouldering and possibly progressing towards secondary progressive.
This talk of smouldering MS gives me hope. If I can help with a clinical trial I’m all ears!
Apr 10, 2022·edited Apr 10, 2022Liked by Gavin Giovannoni
We are new to MS and having found you here, filled with deep gratitude for your work. Really well designed site too.
My son is thirty one, always watched his diet and exercised, and has been in the middle of studying for a stressful professional exam that is intellectually demanding. He has just been diagnosed with MS, one instance of Optic Neuritis two months ago, but in both eyes, separated by a few weeks. He has a handful of lesions too. He is currently waiting to start on Ocrelizumab six monthly, after the team of doctors at Queens Square, London, have one more meeting to confirm their recommendation next week. The turn around between first symptom and now, is 8 weeks. He is in deep shock therefore I am writing.
It feels rather urgent that we get more information on a stronger/more effective treatment based on your understanding of ‘smouldering MS’. He is extremely worried about his brain reducing in size.
Do you have any thoughts on how we broach this issue with the team looking after him so that perhaps they might recommend a more effective treatment?
Re: "Do you have any thoughts on how we broach this issue with the team looking after him so that perhaps they might recommend a more effective treatment?"
All you need to do is push for the most effective treatment on offer. Unfortunately, NHS England limits which treatments can be used depending on how active your MS is, i.e. inactive, active, highly active and rapidly evolving severe. If your son has rapidly-evolving severe MS he may be eligible for other therapies.
I went back and re-read the newsletter from July to tie this one together. Instead of bringing clarification, i am more confused. There is mention in that newsletter of Iron rimmed, black hole type lesions. I have some large, slowly expanding lesions that could be this but my question is about pwMS and anemia. Specifically iron deficient anemia.. Is there a connection there? I was not Dx'd until 2015 but had been showing symptoms since 1987. No one thought to do imaging until 2013 and then only because i had some pretty crazy cognitive issues going on but they would only cover CT scans at that time and I had to wait for better health care coverage in 2015 to get the MRI's which led to my Dx.. The thing is tho that I have been anemic since 1986, sometimes severely so. Recently (Aug 2021) my iron levels were so low my primary doctor was convinced I was bleeding internally (I am not). I started taking liquid Iron with liquid Vitamin C in November and my levels are steadily improving, however, my MRI's have been much worse over this past year.. So I am curious.. Is there any connection between iron deficient anemia and MS? I am SPMS at the moment but rapidly progressing... Last MRI in 30 Sept 2021 showed new lesions (2) on brain stem and 3 (I think) new on neck as well as several new lesions in brain.. I do have a large number of lesions in the brain so not sure that's relevant at the moment if i have 125 or 140 but there are now 6 on the brain stem instead of 4 and 7 on cervical spine instead of 4..
Re: " Is there any connection between iron deficient anaemia and MS?"
No to the best of my knowledge. Iron metabolism is complex and compartmentalised. You can still have excessive iron in your brain and MS lesions and by iron deficient systemically and have anaemia.
For other readers brainstem (posterior fossa) and spinal cord lesions and new disease activity are all associated with poorer outcomes. In general newly documented MS disease activity should trigger a DMT switch to a higher efficacy DMT.
I talk about treating beyond NEIDA (no evident inflammatory disease activity) to target end-organ damage. However, the fact that you are acquiring new lesions is an indication that your have active inflammatory activity and have EIDA (evident inflammatory disease activity) and need an anti-inflammatory therapy to control focal inflammation.
Since I stopped taking Tysabri in 2018, there has been no treatment that has been helpful for me. I came off of Mayzent this past summer because during that 15 months I had 2 relapses and like I said gained 2 brain stem lesions and 3 cervical spinal cord lesions as well as the however many brain lesions. I had symptoms as early as 1987 but was not Dx'd until 2015 so there were decades of damage done because the doctors did not Dx the disease and there fore did not treat me for it. When I was first Dx'd my neurologist couldn't believe I was still walking. That's how bad my MRI's looked.
Feb 3, 2022·edited Feb 3, 2022Liked by Gavin Giovannoni
Really interesting, thank you very much for posting this.
"In patients treated with any DMTs, compared with placebo, proportionally more of the 6mCDW were sustained PIRA events, most notably in RRMS: 65/181 6mCDW (35.9%) in the active arms vs 27/134 (20.0%) in the placebo arms."
Would you have expected this? It would be interesting to know haw the DMTs compare.
Thank you …..so that makes total sense of my experience . Very very bad attack as a juvenile ..total apparent recovery with no further episodes and then steady decline from age 60 to now walking with a stick at 74 .
So the fact that I had it so young has presumably delayed the deterioration that actually seems to occur regardless of DMTs …I had none of course…..
"The more people understand what is happening to their brains and spinal cords despite being on a DMT the better".
Like another commentator below, I have mixed feelings about this - for our mental health, is it really best to be fully informed, and know everything possible about the condition? The truth is, taking this approach (which I have done) can make me feel very bleak about the future... like I'm living with the sword of Damocles over my head.
It can take away the pleasure of my today.
I'm 37, and already had a lot of silent lesions by the point of diagnosis (in 2020), so I've missed the 'early intervention' route and then some. I'm now on ocrelizumab and currently 'fine' on the surface, but I've read enough about MS to know it's likely to hit me like a ton of bricks in the future. Sometimes I wonder if I'd have been better off not reading anything at all... (other days, of course, I'm glad I am informed because it means I feel better able to chase every marginal gain*).
I imagine most pwMS try as best as we can to make healthy choices, so to feel like we are somehow in control of our destinies -- but it is hard sometimes, to suppress the feeling that long-term, you're screwed anyway.
It's a tricky one.
*except a HSCT... my bank balance currently won't allow for that!
I know what you mean. I suspect it the same realisation most people have when they realise they are old and getting older. I am of the opinion that ageing is a disease that can be modified.
Choosing not to know is as important as choosing to find out. It is all about personal, but informed, choice.
I think for myself I would rather know. If I have choices to make and options then I can do something different. Either way I will fight like hell. I won't give up. This disease has taken so much from me now, i refuse to give up willingly what little i have left.
"The more people who understand what is happening to their brains and spinal cords despite being on a DMT the better". Not sure about this one to be honest. Considering that the evolution of treatments to tackle smouldering MS may take 10 years, of what benefit is this knowledge to the patient when they cant do a great deal about it? I understand why it would be better to have wider acceptance amongst the MS community, to push for quicker treatment, to build momentum on the development of drugs etc. I was sat in a room yesterday with one of the leading proponents of HSCT in the UK but the message of watch and wait was essentially still being rolled out. However for the patients with their hands tied and their brain being shredded....its pretty sh*t
Yes and no. Can you tell me why so many pwMS still smoke, don't exercise, eat unhealthily, don't practice intermittent fasting, have poor sleep hygiene, take anti-cholinergics, drink too much, etc. Treating smouldering MS is about so much more than just DMTs and pharmaceuticals.
Point taken, but its works both ways. The informed patient does all these things but MS and the destruction it is causing is always at the front of their mind. There is a balance i suppose, between not making every decision in the context of your disease and giving yourself the best chance.
wait, anti-cholinergics? as in belladonna and magic mushrooms and stuff?
https://gavingiovannoni.substack.com/p/your-anticholinergic-burden
I am more confused now than i was to start with.. for a couple of reasons.. Paroxetine is an SSRI.. I thought.. isnt it? I have been taking this anti depressant on and off cycling thru with a couple of others since I was in my early 30's. I have MDD.. So are SSRI not good either? or is only the Tricyclic antidepressants? SNRI make me nuts so i avoid them and take the SSRIs alone. I actually started having seizures on a combination drug. I am confused but thats not uncommon for me either
What type/window of IF is safe for women when trying for a baby? I've heard it can be quite damaging to a woman's menstrual cycle.
Not sure. It is not recommended, but this recommendation is not evidence based. From an evolutionary perspective I doubt it would be a problem. I have several Muslim patients who have done it during Ramadan and I am aware that it is used by some diabetologists to treat gestational diabetes. Some women, with severe hyperemsis gravidarum, do it any way. I am suspect that not using IF for pregnancy is unlikely to have a major impact on MS.
Thank you for sharing this important article. I have a question: I noticed that in the data sets most DMTs are included but not any IRTs. Do you think that PIRA could be less prevalent amongst IRT patients than with the rest of the treatments? Are there any data on the effect of IRTs on PIRA? Thank you beforehand for your reply.
Thanks for pointing this out! Yes, there is data out there that IRTs, in particular alemtuzumab and AHSCT, when used early in the course of MS seem to have a greater impact on smouldering MS than other DMTs. I suspect the same will hold for cladribine when used early; this is based on the ORACLE or CIS brain volume data and not the CLARITY or RRMS data.
I have always hypothesised that there is something fundamentally different between the mode of action of IRTs and maintenance therapies. We need to find out what this is.
Prof what is the rate of conversion to spms for alem and HSCT please?
It depends on what cohort you choose, the age of treatment and the length of follow-up. The alemtuzumab cohorts that have reported indicate that up to 20% have SPMS at 8 years of follow-up.
Please see: Brown et al. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA. 2019 Jan 15;321(2):175-187. doi: 10.1001/jama.2018.20588.
HSCT data is less clear. However, at 10 years only 55% of the relapsing-remitting cohort are free of progression and by inference the other 45% have SPMS. Please note this cohort will have more advanced disease with more damage before treatment hence the worse outcome compared to alemtuzumab.
Please see: Muraro et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017 Apr 1;74(4):459-469. doi: 10.1001/jamaneurol.2016.5867. PMID: 28241268; PMCID: PMC5744858
Top man, thanks Prof. I know there is no corresponding studies on anti CD20 but it's effectiveness at controlling MRI activity will surely make it difficult to pin point where RRMS ends and SPMS begins
Unfortunately there is no identifiable transition between RRMS and SPMS, they coexist and overlap with each to a greater or lesser extent. This is one of the main messages of the smouldering MS concept that #MS_is_1_not_2_or_3 diseases.
"DMTs only delayed the time from EDSS 1 to 4 (walking problems) by ~3.5 years and time to EDSS 6.0 or a walking stick by ~3.1 years."
Are some DMT's more effective than others at tackling Smouldering MS? Where does Tysabri fit in with effectiveness against smouldering MS? It's consistently said to be one of the most highly effective DMT's but that seems to be mostly just keeping relapses at bay which might not be that effective long term.
as I read that I was thinking about my experience, or I should say nightmare, with Mayzent (siponimod). It was absolute hell, honestly. I took it for 15 months and suffered for 14 of them.. Bad side effects. But really, I had no idea these DMTs only delay disability for that short time. I mean, you have to ask yourself.. Is it it all really worth it?
Super interesting and forwarded this to my MS Nurses in a vain attempt to encourage a conversation with my Neurologist about this later in the month. With the lack of symptoms and an annual MRI, I am a bit lost as what is to be done for my treatment of RRMS. I do not take any DMTs.
I look after my diet with the Overcoming MS wellness program, 20k+ steps daily and yoga 6 times a week and meditation. What more can I do?
That is very interesting given my experience ..I doubt like you I would have been given any DMTs either had they been available then. No further relapses etc…I just felt totally normal again …but initial two episodes meant total paralysis from waist down …
I think I have smouldering MS and it’s the elephant in the room at my neurology appointments.
3+ years post cladribine. Relapsed between Cladribine doses then did well.
However in last 12 months I have had many worstening symptoms incl my mobility. Two bad falls resulting in concussion. Many other debilitating symptoms BUT my MRI in May was stable. My neuro says I’m not eligible for DMTs so I’m getting worse and not able to get treatment. Feel left in no mans land. I have to wait for a relapse to be eligible for more treatment. Meanwhile I’m smouldering and possibly progressing towards secondary progressive.
This talk of smouldering MS gives me hope. If I can help with a clinical trial I’m all ears!
We are new to MS and having found you here, filled with deep gratitude for your work. Really well designed site too.
My son is thirty one, always watched his diet and exercised, and has been in the middle of studying for a stressful professional exam that is intellectually demanding. He has just been diagnosed with MS, one instance of Optic Neuritis two months ago, but in both eyes, separated by a few weeks. He has a handful of lesions too. He is currently waiting to start on Ocrelizumab six monthly, after the team of doctors at Queens Square, London, have one more meeting to confirm their recommendation next week. The turn around between first symptom and now, is 8 weeks. He is in deep shock therefore I am writing.
It feels rather urgent that we get more information on a stronger/more effective treatment based on your understanding of ‘smouldering MS’. He is extremely worried about his brain reducing in size.
Do you have any thoughts on how we broach this issue with the team looking after him so that perhaps they might recommend a more effective treatment?
Re: "Do you have any thoughts on how we broach this issue with the team looking after him so that perhaps they might recommend a more effective treatment?"
All you need to do is push for the most effective treatment on offer. Unfortunately, NHS England limits which treatments can be used depending on how active your MS is, i.e. inactive, active, highly active and rapidly evolving severe. If your son has rapidly-evolving severe MS he may be eligible for other therapies.
Many thanks for your help.
I went back and re-read the newsletter from July to tie this one together. Instead of bringing clarification, i am more confused. There is mention in that newsletter of Iron rimmed, black hole type lesions. I have some large, slowly expanding lesions that could be this but my question is about pwMS and anemia. Specifically iron deficient anemia.. Is there a connection there? I was not Dx'd until 2015 but had been showing symptoms since 1987. No one thought to do imaging until 2013 and then only because i had some pretty crazy cognitive issues going on but they would only cover CT scans at that time and I had to wait for better health care coverage in 2015 to get the MRI's which led to my Dx.. The thing is tho that I have been anemic since 1986, sometimes severely so. Recently (Aug 2021) my iron levels were so low my primary doctor was convinced I was bleeding internally (I am not). I started taking liquid Iron with liquid Vitamin C in November and my levels are steadily improving, however, my MRI's have been much worse over this past year.. So I am curious.. Is there any connection between iron deficient anemia and MS? I am SPMS at the moment but rapidly progressing... Last MRI in 30 Sept 2021 showed new lesions (2) on brain stem and 3 (I think) new on neck as well as several new lesions in brain.. I do have a large number of lesions in the brain so not sure that's relevant at the moment if i have 125 or 140 but there are now 6 on the brain stem instead of 4 and 7 on cervical spine instead of 4..
Re: " Is there any connection between iron deficient anaemia and MS?"
No to the best of my knowledge. Iron metabolism is complex and compartmentalised. You can still have excessive iron in your brain and MS lesions and by iron deficient systemically and have anaemia.
For other readers brainstem (posterior fossa) and spinal cord lesions and new disease activity are all associated with poorer outcomes. In general newly documented MS disease activity should trigger a DMT switch to a higher efficacy DMT.
Re: "... rapidly progressive MS ..."
It sounds like your MS is not being controlled.
I talk about treating beyond NEIDA (no evident inflammatory disease activity) to target end-organ damage. However, the fact that you are acquiring new lesions is an indication that your have active inflammatory activity and have EIDA (evident inflammatory disease activity) and need an anti-inflammatory therapy to control focal inflammation.
Since I stopped taking Tysabri in 2018, there has been no treatment that has been helpful for me. I came off of Mayzent this past summer because during that 15 months I had 2 relapses and like I said gained 2 brain stem lesions and 3 cervical spinal cord lesions as well as the however many brain lesions. I had symptoms as early as 1987 but was not Dx'd until 2015 so there were decades of damage done because the doctors did not Dx the disease and there fore did not treat me for it. When I was first Dx'd my neurologist couldn't believe I was still walking. That's how bad my MRI's looked.
Really interesting, thank you very much for posting this.
"In patients treated with any DMTs, compared with placebo, proportionally more of the 6mCDW were sustained PIRA events, most notably in RRMS: 65/181 6mCDW (35.9%) in the active arms vs 27/134 (20.0%) in the placebo arms."
Would you have expected this? It would be interesting to know haw the DMTs compare.
Just ignore that question, I had a look at fig 2 and now understand that it is the PIRA in the non-relapsing group that is making it higher😊
Thank you …..so that makes total sense of my experience . Very very bad attack as a juvenile ..total apparent recovery with no further episodes and then steady decline from age 60 to now walking with a stick at 74 .
So the fact that I had it so young has presumably delayed the deterioration that actually seems to occur regardless of DMTs …I had none of course…..
This was packed with information, thanks. Appreciate it and your honesty and delivery.