Yes, we need to go beyond the B-cell. We can’t accept the status quo and think we have sorted MS out because most pwMS treated early with MS are NEIDA.
I agree that just using NEIDA as an endpoint for effectiveness of DMT treatment is just scratching the surface. I am in the SAW category, but fortunately it's been very slow progression. I like your theory of EBV being the essential necessity for developing MS. That is a major shift for opening up a whole class of new treatments. The medical profession will resist as they did in resisting the discovery of helicobacter causing ulcers rather than stress. All us MSers want the progressing disability to STOP. Please make it stop!
Hello Joan, same here. Couldn’t put it better. Thankfully, it’s been a relatively slow decline since I was NEIDA and “cured”. But it’s declining! Brain function is my greatest worry…🌷
I now understand what bothered me about the approach I saw in the French neurology professors I read on social networks or heard via webinar. No one has ever talked about trying to understand the origins of MS and the progression, let alone changing the paradigm of even RR treatment. It's sad. One does not expect such reflections from frontline neurologists - they apply the protocol. But I would have expected more reflections from the professors. Perhaps they reserve their reflections for discussion among the experts. However, the sentence pronounced by a professor to summarise a symposium on MS treatments held in France recently - we are beginning to have ideas concerning progressive MS - saddens me because the disease has existed for centuries and we are just beginning to have ideas!!!. Ok. They are doing their job well: they test pharmaceutical companies' products and try to manage MS the symptoms, but I ask myself why there are not more committed professors like Prog Giavanonni to make things move forward ?
May 9, 2023·edited May 9, 2023Liked by Gavin Giovannoni
ProfG is a maverick and most other neurologists detach themselves from the patient experience otherwise they'd go mad. Play it safe, follow the protocol, advance science in tiny steps, retire and collect your pension. MS becomes an abstract concept that "patients" have.
The moment you consider, "There but for the grace of God go I", is the moment where you have to push the envelope, have to take risks (always with fully informed patient consent) and what patient wants to end up as a statistic?
Better to take the risk, join the trial, treat the undesired effects than leave the brain to rot as we tiptoe slowly, painfully slow step by painfully slow step, for decades and decades and decades.
Most neurologists can't stand ProfG because he turns the whole patient-specialist relationship on its head. Empowering patients whose prognosis, even at the most optimistic, is grim (or at least was grim) - is what has got us where we are now. With patients pushing for more efficacy and for appreciation that the risk side of risk-benefit includes the risk of the disease itself (revolutionary outside of oncology).
As a patient I was originally very risk averse and it has cost me immeasurably. I have now learned the error of my ways and lean the opposite way. Sadly in the country to which I've moved, most specialists and professors remain extremely conservative in their approach to risk, requiring a level of grandstanding on my part for which I supposedly lack the adequate education to carry any gravitas. Mentioning ProfG by name usually elicits a derogatory response but inevitably ends up with the desired solution, switching to a treatment that will hopefully extend my active life as long as possible. While managing the risks as best we can.
I couldn't get Alumtuzumab in Yorkshire. So I asked my neurologist who the best MS neurologist in the UK is. He said Prof G. So I moved to London for treatment 🤷
One way or another the mere mention of your name seems to (eventually) get the desired response out of overly-cautious neurologists. Long live the messenger!
I fully agree with your observations. In particular regarding the impossibility for a patient to participate in the benefit-risk balance. I can understand that in the welfare states the overall treatment budget is important (knowing that 30% of patients will stay on the first line medication, the system will be a budget winner) but to impose on us a treatment we don't want on the pretext of our well-being is another thing.
I also agree that for a number of doctors MS remains an abstract thing, they want to retire without taking the risk. If we believe the statistics, only about 40 cases of HSCT have been performed in France, under the pretext that it leads to 1% of deaths. Here again, it is not the budget of the health system that is being put forward but our "well-being" as patients, without anyone asking us if we agree to bear the risk.
I can also admit that countries may have different research patterns that would not involve practitioners directly in the research. But even in countries where this possibility is offered to practitioners, many will not bother because of the administrative complexity.
Finally, I don't come from a medical background but in my profession we also have the degree of 'professor'. So I'm never intimidated by the title that can often be awarded through allegiance to the system and the accumulation of knowledge. I am just sad that these indifferent people have the same power to act as those who want to take things forward.
Simon, I was on the least effective drug, due to my age. Perhaps I should have pushed for a better DMT later, but there weren’t many at the time. I understand. As Prof G says, “time is brain”. (I think I got that right.)
When would you think about switching to alemtuzumab in this situation? I find that my team is not really offering this after I had to switch off tysabri for JC virus titer spike and am very attracted to this therapeutic option!
Yes, me too. I was told in 2021 that my centre no longer offers alemtuzumab b/c of safety profile (although when I last had my infusion, there was a woman next to me having a third year of it as she'd had further activity). Would there be a significant PML risk with such a move, though? (I'm just thinking of what I once read on MS-Selfie, about JC levels not able to be gauged post-ocrelizumab.)
Personally: I'm grateful to be on ocrelizumab but I am starting to contemplate long-term safety so good food for thought in this newsletter. (Re: teriflunomide - would patients have to wait until B-cells repopulated before starting on such a treatment?)
As a person with ms on anti cd20 I agree. It has been an amazing evolution but is by no means a cure and we cannot get complacent. And choosing between life in a mask always being on the outside or repeated covid infections always feeling sick is no way to live. You have to give up normal life while watching others live and feeling like life is passing you by.
Time is brain, as you say. Thank you for fighting the good fight.
'We can’t accept the status quo and think we have sorted MS out because most pwMS treated early with MS are NEIDA.'
The gigantic problem is that some people with MS aren't treated early. The NHS denied me access to an MS disgnosis for decades, since I was a child; I was severely disabled the entire time. One can call it gaslighting or gross medical negligence.
I have 'significant cerebral atrophy'. I've just had Alemtuzumab; it might stop me getting worse, but hasn't made me better. Is it considered too late for someone like me, and too hard to try undo damage already done? Is research being done to help people who had untreated MS for many, many years? 🤕
There will probably always be people like me, outliers, who have been denied healthcare. Because of where we are in the world (Yorkshire in my case...), our socioeconomic status, and abuse by family and doctors. What of us?
I like the term SAW and that it rhymes with RAW is a bonus. At the end of the day it's the same as old-fashioned 'progression' which always seems ironic as progression is usually taken to be a positive!
I was thinking about this newsletter in the middle of the night (probably because this time next week I'll be having dose #5). It's made me feel a bit low, TBH - but I guess this is the risk we take when we try to read as much as possible about our condition: it can occasionally dent the optimism that feels integral to living well with MS.
Anyway, I'll try to shake off the blues and look at this pragmatically: do other patients understand my hypothetical reluctance to de-risk to a less effective therapy (e.g. teriflunomide), because then I might not be able to access highly effective therapies in future? When it's being drummed into our heads to hit MS hard, it feels like a strange decision to actively make. Similarly, it's also crossed my mind: in future, would I be less likely to be able to access BTKis if I de-risked?
(On another note: it's the cancer risk that makes me feel apprehensive about L/T ocrelizumab use. Am I naive to presume that there's some central database which is keeping tabs on this data....?!)
Re: "Am I naive to presume that there's some central database which is keeping tabs on this data....?"
Yes and no. Some countries track this data as part of routine clinical practice (Nordics) and in North America it collected as part of insurance claims and some HMOs do it as part of routine care (e.g. Kaiser). Roche is doing an extension study and in the UK we are doing a national pharmacovigilance study. So there are multiple data sources that can track the safety of ocrelizumab. FYI it was the Swedish registry that showed that serious infections were much commoner with rituximab than other DMTs. As for cancer risk the jury is out on this and at present there is no clear signal. If a cancer risk emerges it will be relatively small. A bigger risk would have been seen already.
The title is very misleading. If you read the small print and look at the differences in slopes between pwMS and healthy controls pwMS are losing brain much more rapidly than healthy controls and BVL in pwMS is not in the normal range. The authors protect themselves by using the word similar.
May 9, 2023·edited May 9, 2023Liked by Gavin Giovannoni
Prof G,
I have convinced my centre to switch me from Ocrevus to Lemtrada following your articles.
Do you think alemtuzumab has, in a young person, early in their diagnosis, the potential to stop smouldering MS and BVL?
Or, do you think it is merely the best available option that simply *may* impact smouldering MS (I.e. would it be better to hold out on Ocrevus and wait for BTKis?)?
Re: "Or, do you think it is merely the best available option that simply *may* impact smouldering MS (I.e. would it be better to hold out on Ocrevus and wait for BTKis?)?"
Waiting for the BTKIs is a gamble. There are still issues with the class in terms of potential liver toxicity and other yet to be defined adverse events (unknown unknowns).
Great stuff. You had enthusiastically highlighted NfL testing very recently…can you share some thoughts regarding the degree of importance would you assign to sNfL testing results following a decision to de-risk an individual? As important as MRI, perhaps? Annually? Finally…any enthusiasm regarding plasma GFAP testing in addition?
NFL is just another inflammatory marker and will allow you to monitor recurrent disease activity remotely and more frequently than MRI. It will be a game changer.
I like SAW, because that’s exactly where I am. NEID and extremely frustrated not to mention getting worse. NEID does not mean “cured” now go away, end of, although that’s the standard of treatment, if you want to call it that. We can have huge flares with NEID and nothing to turn to. It’s a terrible situation for those who have been fortunate enough to achieve first rate responses to good DMTs only to lose what you’ve gained or progress you’ve made. You’re “cured” because the goal is NEID? No you’ll be SAW!!
“I am predicting relative to teriflunomide as a class, BTKIs will reduce disability progression by about 45% (range 40-60%).” Doesn’t sound that impressive to me! Would you be happy knowing that your brain / spinal cord was still being shredded (albeit slightly slower) despite being on anti-CD20 and BTKi therapies? What’s needed to ‘stop’ disability progression ie 100%? Will anti-virals make a greater impact on reducing disability progression?
Don't forget that teriflunomide reduces disease progression compared to placebo by 25-30% already and probably gets better with time. So this is on top of the 30%; i.e. compared to placebo this would be a 75% reduction in confirmed disability progression. This would be impressive. But I may be proved wrong. However, based on the basic science intrathecal B-cells and activated microglia are legitimate treatment targets for SAW so lets be optimistic. I am told experts often under estimate the effects of a new innovation so lets hope it is even better.
Sounds very positive. Please can you send me a prescription for BTK inhibitors so that I can get started. I can’t wait another 3-4 years and “time is brain”.
I agree with you prof G. Lesions are not the heart of MS. Maybe the real MS is the "thing" that drives progression in PPMS or non active SPMS patients (who have or dont have lesions but still their MS is progressing). I really would like BTK be very effective in PPMS. There are limited options for patients with this form :-( Do you think that BTK can be effective in PPMS? Or not because in this form people have antibodies in CSF which can drive their MS?
I agree that just using NEIDA as an endpoint for effectiveness of DMT treatment is just scratching the surface. I am in the SAW category, but fortunately it's been very slow progression. I like your theory of EBV being the essential necessity for developing MS. That is a major shift for opening up a whole class of new treatments. The medical profession will resist as they did in resisting the discovery of helicobacter causing ulcers rather than stress. All us MSers want the progressing disability to STOP. Please make it stop!
Well said. I too believe in the viral origin. Stop the virus stop the silent damage
Hello Joan, same here. Couldn’t put it better. Thankfully, it’s been a relatively slow decline since I was NEIDA and “cured”. But it’s declining! Brain function is my greatest worry…🌷
I now understand what bothered me about the approach I saw in the French neurology professors I read on social networks or heard via webinar. No one has ever talked about trying to understand the origins of MS and the progression, let alone changing the paradigm of even RR treatment. It's sad. One does not expect such reflections from frontline neurologists - they apply the protocol. But I would have expected more reflections from the professors. Perhaps they reserve their reflections for discussion among the experts. However, the sentence pronounced by a professor to summarise a symposium on MS treatments held in France recently - we are beginning to have ideas concerning progressive MS - saddens me because the disease has existed for centuries and we are just beginning to have ideas!!!. Ok. They are doing their job well: they test pharmaceutical companies' products and try to manage MS the symptoms, but I ask myself why there are not more committed professors like Prog Giavanonni to make things move forward ?
ProfG is a maverick and most other neurologists detach themselves from the patient experience otherwise they'd go mad. Play it safe, follow the protocol, advance science in tiny steps, retire and collect your pension. MS becomes an abstract concept that "patients" have.
The moment you consider, "There but for the grace of God go I", is the moment where you have to push the envelope, have to take risks (always with fully informed patient consent) and what patient wants to end up as a statistic?
Better to take the risk, join the trial, treat the undesired effects than leave the brain to rot as we tiptoe slowly, painfully slow step by painfully slow step, for decades and decades and decades.
Most neurologists can't stand ProfG because he turns the whole patient-specialist relationship on its head. Empowering patients whose prognosis, even at the most optimistic, is grim (or at least was grim) - is what has got us where we are now. With patients pushing for more efficacy and for appreciation that the risk side of risk-benefit includes the risk of the disease itself (revolutionary outside of oncology).
As a patient I was originally very risk averse and it has cost me immeasurably. I have now learned the error of my ways and lean the opposite way. Sadly in the country to which I've moved, most specialists and professors remain extremely conservative in their approach to risk, requiring a level of grandstanding on my part for which I supposedly lack the adequate education to carry any gravitas. Mentioning ProfG by name usually elicits a derogatory response but inevitably ends up with the desired solution, switching to a treatment that will hopefully extend my active life as long as possible. While managing the risks as best we can.
Please don't shoot the messenger.
I couldn't get Alumtuzumab in Yorkshire. So I asked my neurologist who the best MS neurologist in the UK is. He said Prof G. So I moved to London for treatment 🤷
Why would I do that?
One way or another the mere mention of your name seems to (eventually) get the desired response out of overly-cautious neurologists. Long live the messenger!
I fully agree with your observations. In particular regarding the impossibility for a patient to participate in the benefit-risk balance. I can understand that in the welfare states the overall treatment budget is important (knowing that 30% of patients will stay on the first line medication, the system will be a budget winner) but to impose on us a treatment we don't want on the pretext of our well-being is another thing.
I also agree that for a number of doctors MS remains an abstract thing, they want to retire without taking the risk. If we believe the statistics, only about 40 cases of HSCT have been performed in France, under the pretext that it leads to 1% of deaths. Here again, it is not the budget of the health system that is being put forward but our "well-being" as patients, without anyone asking us if we agree to bear the risk.
I can also admit that countries may have different research patterns that would not involve practitioners directly in the research. But even in countries where this possibility is offered to practitioners, many will not bother because of the administrative complexity.
Finally, I don't come from a medical background but in my profession we also have the degree of 'professor'. So I'm never intimidated by the title that can often be awarded through allegiance to the system and the accumulation of knowledge. I am just sad that these indifferent people have the same power to act as those who want to take things forward.
Simon, I was on the least effective drug, due to my age. Perhaps I should have pushed for a better DMT later, but there weren’t many at the time. I understand. As Prof G says, “time is brain”. (I think I got that right.)
When would you think about switching to alemtuzumab in this situation? I find that my team is not really offering this after I had to switch off tysabri for JC virus titer spike and am very attracted to this therapeutic option!
Yes, me too. I was told in 2021 that my centre no longer offers alemtuzumab b/c of safety profile (although when I last had my infusion, there was a woman next to me having a third year of it as she'd had further activity). Would there be a significant PML risk with such a move, though? (I'm just thinking of what I once read on MS-Selfie, about JC levels not able to be gauged post-ocrelizumab.)
Personally: I'm grateful to be on ocrelizumab but I am starting to contemplate long-term safety so good food for thought in this newsletter. (Re: teriflunomide - would patients have to wait until B-cells repopulated before starting on such a treatment?)
As a person with ms on anti cd20 I agree. It has been an amazing evolution but is by no means a cure and we cannot get complacent. And choosing between life in a mask always being on the outside or repeated covid infections always feeling sick is no way to live. You have to give up normal life while watching others live and feeling like life is passing you by.
Time is brain, as you say. Thank you for fighting the good fight.
'We can’t accept the status quo and think we have sorted MS out because most pwMS treated early with MS are NEIDA.'
The gigantic problem is that some people with MS aren't treated early. The NHS denied me access to an MS disgnosis for decades, since I was a child; I was severely disabled the entire time. One can call it gaslighting or gross medical negligence.
I have 'significant cerebral atrophy'. I've just had Alemtuzumab; it might stop me getting worse, but hasn't made me better. Is it considered too late for someone like me, and too hard to try undo damage already done? Is research being done to help people who had untreated MS for many, many years? 🤕
There will probably always be people like me, outliers, who have been denied healthcare. Because of where we are in the world (Yorkshire in my case...), our socioeconomic status, and abuse by family and doctors. What of us?
I like the term SAW and that it rhymes with RAW is a bonus. At the end of the day it's the same as old-fashioned 'progression' which always seems ironic as progression is usually taken to be a positive!
Yes, progression is a misnomer and should be dropped from the MS lexicon. It means different things to different people and is holding back the field.
Yes, another word should be used. Progression is not usually concomitant with worsening. The word needs to be something very alarming.
I was thinking about this newsletter in the middle of the night (probably because this time next week I'll be having dose #5). It's made me feel a bit low, TBH - but I guess this is the risk we take when we try to read as much as possible about our condition: it can occasionally dent the optimism that feels integral to living well with MS.
Anyway, I'll try to shake off the blues and look at this pragmatically: do other patients understand my hypothetical reluctance to de-risk to a less effective therapy (e.g. teriflunomide), because then I might not be able to access highly effective therapies in future? When it's being drummed into our heads to hit MS hard, it feels like a strange decision to actively make. Similarly, it's also crossed my mind: in future, would I be less likely to be able to access BTKis if I de-risked?
(On another note: it's the cancer risk that makes me feel apprehensive about L/T ocrelizumab use. Am I naive to presume that there's some central database which is keeping tabs on this data....?!)
Re: "Am I naive to presume that there's some central database which is keeping tabs on this data....?"
Yes and no. Some countries track this data as part of routine clinical practice (Nordics) and in North America it collected as part of insurance claims and some HMOs do it as part of routine care (e.g. Kaiser). Roche is doing an extension study and in the UK we are doing a national pharmacovigilance study. So there are multiple data sources that can track the safety of ocrelizumab. FYI it was the Swedish registry that showed that serious infections were much commoner with rituximab than other DMTs. As for cancer risk the jury is out on this and at present there is no clear signal. If a cancer risk emerges it will be relatively small. A bigger risk would have been seen already.
Speaking of BVL....what about this recent study?
https://pubmed.ncbi.nlm.nih.gov/37148240/
The title is very misleading. If you read the small print and look at the differences in slopes between pwMS and healthy controls pwMS are losing brain much more rapidly than healthy controls and BVL in pwMS is not in the normal range. The authors protect themselves by using the word similar.
Annualised BVL of matched ocrelizumab-treated patients with relapsing multiple sclerosis vs healthy controls −1.63/cm3 pa [95%CI = −3.27; −0.15].
Prof G,
I have convinced my centre to switch me from Ocrevus to Lemtrada following your articles.
Do you think alemtuzumab has, in a young person, early in their diagnosis, the potential to stop smouldering MS and BVL?
Or, do you think it is merely the best available option that simply *may* impact smouldering MS (I.e. would it be better to hold out on Ocrevus and wait for BTKis?)?
Thanks for all your work.
Re: "Do you think alemtuzumab has, in a young person, early in their diagnosis, the potential to stop smouldering MS and BVL?"
Yes, which is why I think it should be offered to pwMS more often. However, it is not for everyone in terms of its associated risks.
Re: "Or, do you think it is merely the best available option that simply *may* impact smouldering MS (I.e. would it be better to hold out on Ocrevus and wait for BTKis?)?"
Waiting for the BTKIs is a gamble. There are still issues with the class in terms of potential liver toxicity and other yet to be defined adverse events (unknown unknowns).
Great stuff. You had enthusiastically highlighted NfL testing very recently…can you share some thoughts regarding the degree of importance would you assign to sNfL testing results following a decision to de-risk an individual? As important as MRI, perhaps? Annually? Finally…any enthusiasm regarding plasma GFAP testing in addition?
NFL is just another inflammatory marker and will allow you to monitor recurrent disease activity remotely and more frequently than MRI. It will be a game changer.
I like SAW, because that’s exactly where I am. NEID and extremely frustrated not to mention getting worse. NEID does not mean “cured” now go away, end of, although that’s the standard of treatment, if you want to call it that. We can have huge flares with NEID and nothing to turn to. It’s a terrible situation for those who have been fortunate enough to achieve first rate responses to good DMTs only to lose what you’ve gained or progress you’ve made. You’re “cured” because the goal is NEID? No you’ll be SAW!!
“I am predicting relative to teriflunomide as a class, BTKIs will reduce disability progression by about 45% (range 40-60%).” Doesn’t sound that impressive to me! Would you be happy knowing that your brain / spinal cord was still being shredded (albeit slightly slower) despite being on anti-CD20 and BTKi therapies? What’s needed to ‘stop’ disability progression ie 100%? Will anti-virals make a greater impact on reducing disability progression?
Don't forget that teriflunomide reduces disease progression compared to placebo by 25-30% already and probably gets better with time. So this is on top of the 30%; i.e. compared to placebo this would be a 75% reduction in confirmed disability progression. This would be impressive. But I may be proved wrong. However, based on the basic science intrathecal B-cells and activated microglia are legitimate treatment targets for SAW so lets be optimistic. I am told experts often under estimate the effects of a new innovation so lets hope it is even better.
Sounds very positive. Please can you send me a prescription for BTK inhibitors so that I can get started. I can’t wait another 3-4 years and “time is brain”.
The results of the first trials will be out in 2024 and commercially available 12-24 months after that. So you are right 3-4 years time.
Does mavenclad not target both b and t cells?
I agree with you prof G. Lesions are not the heart of MS. Maybe the real MS is the "thing" that drives progression in PPMS or non active SPMS patients (who have or dont have lesions but still their MS is progressing). I really would like BTK be very effective in PPMS. There are limited options for patients with this form :-( Do you think that BTK can be effective in PPMS? Or not because in this form people have antibodies in CSF which can drive their MS?