It is important to debunk this analysis of rituximab vs. cladribine because both agents are on the WHO’s essential medicine list (EML) as treatments for MS.
The rituximab vs cladribine study is super disappointing to me, because I feel like clinicians significantly discount the general risks of maintenance/escalation therapy. Maybe that's because they are used to those risks, and because the risks used to apply to all the available therapies. But they're no longer part of the calculus for all DMTs, because IRT is available.
Those risks also differ wildly depending on personal circumstances. I'm in the US and finished my IRT last year. My employment situation, and therefore my healthcare situation, is not stable. If I were on a maintenance/escalation therapy, I'd be terrified at what is happening to the healthcare system. As it is, I have a _very_ good chance that I won't need anything for years. Maybe never. I might have trouble getting all the follow-up I should have, but that's very different from having to fight insurance for access to a DMT, go through step therapy, etc.
We're also having a resurgence of antivax sentiment. I am on Team Vaccine. Not needing to worry about long-term immune suppression, and being able to get vaccinated myself, is really important to me. That's on top of all the other infections so common in people with MS. And with maintenance/escalation therapy, you're likely going to be going to hospitals/pharmacies a lot more than someone who did IRT, which means more time spent around people with infections. I'm 99.9% sure my one Covid infection came from the hospital.
Nothing is certain. I could "fail" cladribine, have a major relapse that means I need more medical attention, for some reason be unable to try the other IRT (Lemtrada, right?). Maybe copaxone (the escalation/maintenance DMT I was initially offered and refused) would have been perfect for me and never had any side effects or need to switch. But I feel like I picked the tradeoffs I could live with, and I'm concerned that so many people just don't even seem to _see_ those tradeoffs. I am all for informed consent, just... the information seems pretty bad.
I came from a time and place (early 2000's, California) where I was able to experience growing up, and through, all the different therapies/modalities--although I didn't try every one, as they weren't all applicable, and some scared the bejeebers out of me (like Novantrone). I even remember when Tysabri was originally called Antegren. I wish I had the option of an IRT in the beginning, like aHSCT, or cladribine, or even Lemtrada. But by the time they were available I was too disease addled, and immunocompromised to try--though I did recently try one round of cladribine, but it did very little for me at this point (I'm at 8.0/8.5 on EDSS scale). I could have tried stem cell therapy in 2010, but the facilities worried me, and I couldn't afford the procedure anyway. The main point I want to get across to anyone is to use the most potent therapy available as early as possible. There just isn't any time for anything else... except regret.
I find this article particularly interesting, Prof G. My own neurologist is keen for me to begin Rituximab within the coming weeks, yet I remain deeply hesitant. I live with several other autoimmune conditions, which he believes Rituximab may also help to manage. However, while I fully acknowledge the potential of high-efficacy therapies to reduce both focal inflammation and PIRA, I can't help but question the broader impact, namely, the cost to a patient’s overall health, particularly in terms of increased infection risk.
Are they truly worth it? Perhaps. Although it is exceptionally hard as a patient to accept such risk when you don’t feel your MS is “too bad,” but know you are vulnerable to something far more frightening, such as an adrenal crisis, should an infection get out of hand. I just wish there were more open discussion and deeper understanding of the impact these treatment decisions can have on patients and their families. Comparing relative efficacy is one thing, but it risks dehumanising what is, for many of us, a personal and often daunting process.
Anti CD20 risks (and linked to that, monitoring needs) are overall fairly low - at least for the first few rounds. That's one of the (the main?) reasons neuros like them so much.
Having said that, after 6 years of ocrelizumab I would not mind switching - the infection risk increases over time. And being able to get decent vaccine response would be nice, too (looking at shingrix in particular).
Thank you for another informative and fascinating article Prof G. Does this suggest, as per your one disease theory, that DMTs shouldn’t be so strictly ring fenced to ‘versions’ of MS but considered for all pwMS such as those with PPMS/SPMS/SAW?
“This data suggests that what is happening in the spinal cord in terms of MS pathology is different to what is happening in the brain. If this is the case, we will have to rethink spinal cord pathology in MS.”
Every time I think we are near to understanding / effectively treating this disease, it springs another surprise! I assumed brain tissue and spinal cord tissue were the same and that the mechanisms causing tissue damage were the same. Are anti-CD20 therapies and BTK inhibitors having any impact on the mechanisms behind spinal cord atrophy? Are you suggesting that different therapies may be required to tackle tissue damage in the spinal cord?
They are somewhat the same, and they aren't... I know it's confusing. one of the biggest differences has to do with the mitochondria of the neurons, and the mitochondrial dysfunction is a big part of multiple sclerosis. This might help explain a little more:
Metabolic Differences:
Spinal cord mitochondria show lower rates of oxidative phosphorylation compared to brain mitochondria, potentially due to lower levels of respiratory complexes, according to a study published in the American Physiological Society Journal. They also accumulate less calcium and generate more reactive oxygen species (ROS) with certain substrates.
Vulnerability to Damage:
The differences in calcium handling and ROS production suggest spinal cord mitochondria may be more vulnerable to oxidative damage and calcium overload under certain conditions. This could contribute to the increased susceptibility of spinal cord motor neurons in conditions like amyotrophic lateral sclerosis (ALS).
Functional Distinctions:
The study also indicates that spinal cord mitochondria have lower Ca2+ accumulation capacity and generate more ROS than brain mitochondria, particularly when utilizing specific substrates.
Morphological Differences:
Research suggests that mitochondrial morphology can vary within neurons, with distinct shapes observed in dendrites and axons. During neural differentiation, mitochondria reshape from short and thick to thinner and elongated, forming a more complex network.
Also important, although somewhat different, are the functions of the neurons and interneurons in the brain and spinal cord. While both the brain and spinal cord contain sensory and motor neurons, carrying the signals for sensory and motor functions are primarily the purview of the spinal cord, and the brain neurons control many functions at once other than just processing sensory information and sending out motor signals. The brain is the computer (CPU), and the spinal cord is all of the cables. And the constituent neurons reflect that. This last part I probably got some of it wrong, as I haven't been in school for a long time, and I wasn't the greatest student.
I’m in australia and I get brain and spinal cord in all my annual MRIs. Been doing that for 4 years now. Thankfully steady
The gd aspect does make me nervous however I’ve switched to non contrast now as things have settled down
The one thing I keep debating and good to get your view is tysabri > cladribine. I’m stable and doing really well on NTZ but the thought of going to cladribine whilst I’m JC negative and stable is appealing however I’m concerned about rebound activity and potentially doing worse by poking the bear. My neurologist is supportive of what I decide to do but it’s the million dollar question
All my visible lesions are in my spinal cord, my brain still shows now lesions in MRIs after 12 years of MS. Their shape doesn''t indicate NMOSD though and I've been negative for aquaporin-4-antibodies. Out of my four spinal cord lesions (three in C-spine, one in T-spine) only one was connected to a clear relapse - the others were either asymptomatic or mistaken for paroxysmal symptoms. I'm just saying this, because without spinal cord MRIs I'm not sure I'd even have an MS diagnosis and therefore access to DMTs to prevent further damage.
I am having trouble because I seem to have a neurologist who doesn't really care to stay completely on top of things. Every time I call with questions--which is pretty infrequently--he never seems to have the time to call me back, and I have to figure out things on my own. Recently as a couple of weeks ago my symptoms of muscle weakness, and contracture, have become markedly worse. But I have I don't know whether to understand this as a relapse, or just the normal course of progression. And my neurologist is really not helping in this regard.
I do understand that relapses are described as new symptoms or reawakened old symptoms that persist for 24 hours or more. But that leaves things open ended, as it doesn't explain the other side of me equation. I guess I'll show explain it this way: I understand the end result of a relapse definition as something that persists for 24 hours or more. But deciding whether something is a relapse or just worsening progression, how is that is decided from the way that symptoms present themselves? An example would be that my hands have been getting worse for some time now, but recently they got a lot worse, and I don't really notice that I have any new infections or something else that have possibly initiated this. So how can I tell which is which, to inform my next step? I have read somewhere that relapses can last anywhere from days to months. That does not bode well as whatever is causing something below the surface, it could be adding to ongoing damage that will be permanent. And worsening progression just come on suddenly, and just persist? Or does it come on slowly or very slowly? Or perhaps it vacillates back and forth between slow and quickly? This is all very concerning and really stressful.
I have never tried rituximab, but I have gone on mavenclad before. I wasn't able to continue the Mavenclad though for more than one year because of issues with chronic bladder infections. Like I said I never tried rituximab, but early in my disease my then neurologist decided to try cyclophosphamide Because she had done a ton of research trying to catch up with new ideas in MS research, as she was only a general neurologist and really didn't know very much about multiple sclerosis. This was in 2002. She was on to something, but this was still somewhat outlier type of thinking at the time. She also tried things like Cellcept to hopefully help me arrest the disease progression. Pretty forward thinking for someone who was somewhat out of their wheelhouse. You make very good points professor G: we need all the effective medications for multiple sclerosis, and pitting them against each other has no real value when the experiments are not designed well. The point that there are generic equivalents is especially salient since there are so many peole who are economically disadvantaged that need access to effective medications, and can't afford leading brand, high efficacy therapies.
Thanks Prof G, this was really useful. I've just had my first head MRI, 6 months after starting Siponimod. I hadn't considered that this would be a new baseline, and had wondered how my Neurologist would know when any new lesions occurred, especially given that it took 15 months from my previous MRI to actually start the medication. It now makes perfect sense!
I've never had an MRI with contrast. Is that the same as Gd? Theyve all just been the MRI process, originally of head,, then head and C-spine, then head and whole spine. My baseline at the new hospital in September 2023 was head and whole spine, but I knew going forward that it would just be head. I assumed this was just a different policy to the previous hospital, but there would appear to be a need to research whether whole spine MRI is useful and therefore necessary.
Hi Prof Giovannoni and thank you for the nice article!
Is it true for cladribine that if you don't have relapses at the fourth year, like today have taken the first course in September 2021, it is less likely that the drug will fail you within a window of 10 years?
ProfG, would love to read a deep dive on Gd for monitoring... My neuro still insists on it, personally I have a fair bit of skepticism. I think part of the reasoning is that if one could catch an active lesion, there would be a discussion to be had that ocr failed (but I am not too sure it's helping all that much to begin with).
It'd be interesting to know in which part of the spinal cord were detected those lesions (not causing relapses), if it's mostly C spine or other parts as well. At least in our country they mostly include C spine along with brain when doing regular monitoring and study I was participating in also had included C spine.
I think there was an attack ms trial going on where as soon as people were diagnosed with ms they were put straight on tysabri as I believe it’s one of the fastest acting dmts ?
so mri from diagnosis and the new baseline say 6months later should hopefully show no new lesions would that not be the best option for those newly diagnosed if jcv - then transition to another dmt such as cladribine to give the best chance of controlling new lesions from the start ?
Also do patients always have to wait for cladribine to fail them before being offered another dmt?
could they start one of the lower efficacy dmts with lower associated risks say tecfidera to keep the monsters at bay say 2 years after completion on cladribine? Apologies if I’ve gone of course
The rituximab vs cladribine study is super disappointing to me, because I feel like clinicians significantly discount the general risks of maintenance/escalation therapy. Maybe that's because they are used to those risks, and because the risks used to apply to all the available therapies. But they're no longer part of the calculus for all DMTs, because IRT is available.
Those risks also differ wildly depending on personal circumstances. I'm in the US and finished my IRT last year. My employment situation, and therefore my healthcare situation, is not stable. If I were on a maintenance/escalation therapy, I'd be terrified at what is happening to the healthcare system. As it is, I have a _very_ good chance that I won't need anything for years. Maybe never. I might have trouble getting all the follow-up I should have, but that's very different from having to fight insurance for access to a DMT, go through step therapy, etc.
We're also having a resurgence of antivax sentiment. I am on Team Vaccine. Not needing to worry about long-term immune suppression, and being able to get vaccinated myself, is really important to me. That's on top of all the other infections so common in people with MS. And with maintenance/escalation therapy, you're likely going to be going to hospitals/pharmacies a lot more than someone who did IRT, which means more time spent around people with infections. I'm 99.9% sure my one Covid infection came from the hospital.
Nothing is certain. I could "fail" cladribine, have a major relapse that means I need more medical attention, for some reason be unable to try the other IRT (Lemtrada, right?). Maybe copaxone (the escalation/maintenance DMT I was initially offered and refused) would have been perfect for me and never had any side effects or need to switch. But I feel like I picked the tradeoffs I could live with, and I'm concerned that so many people just don't even seem to _see_ those tradeoffs. I am all for informed consent, just... the information seems pretty bad.
I came from a time and place (early 2000's, California) where I was able to experience growing up, and through, all the different therapies/modalities--although I didn't try every one, as they weren't all applicable, and some scared the bejeebers out of me (like Novantrone). I even remember when Tysabri was originally called Antegren. I wish I had the option of an IRT in the beginning, like aHSCT, or cladribine, or even Lemtrada. But by the time they were available I was too disease addled, and immunocompromised to try--though I did recently try one round of cladribine, but it did very little for me at this point (I'm at 8.0/8.5 on EDSS scale). I could have tried stem cell therapy in 2010, but the facilities worried me, and I couldn't afford the procedure anyway. The main point I want to get across to anyone is to use the most potent therapy available as early as possible. There just isn't any time for anything else... except regret.
I find this article particularly interesting, Prof G. My own neurologist is keen for me to begin Rituximab within the coming weeks, yet I remain deeply hesitant. I live with several other autoimmune conditions, which he believes Rituximab may also help to manage. However, while I fully acknowledge the potential of high-efficacy therapies to reduce both focal inflammation and PIRA, I can't help but question the broader impact, namely, the cost to a patient’s overall health, particularly in terms of increased infection risk.
Are they truly worth it? Perhaps. Although it is exceptionally hard as a patient to accept such risk when you don’t feel your MS is “too bad,” but know you are vulnerable to something far more frightening, such as an adrenal crisis, should an infection get out of hand. I just wish there were more open discussion and deeper understanding of the impact these treatment decisions can have on patients and their families. Comparing relative efficacy is one thing, but it risks dehumanising what is, for many of us, a personal and often daunting process.
Truly.
Anti CD20 risks (and linked to that, monitoring needs) are overall fairly low - at least for the first few rounds. That's one of the (the main?) reasons neuros like them so much.
Having said that, after 6 years of ocrelizumab I would not mind switching - the infection risk increases over time. And being able to get decent vaccine response would be nice, too (looking at shingrix in particular).
Thank you for another informative and fascinating article Prof G. Does this suggest, as per your one disease theory, that DMTs shouldn’t be so strictly ring fenced to ‘versions’ of MS but considered for all pwMS such as those with PPMS/SPMS/SAW?
“This data suggests that what is happening in the spinal cord in terms of MS pathology is different to what is happening in the brain. If this is the case, we will have to rethink spinal cord pathology in MS.”
Every time I think we are near to understanding / effectively treating this disease, it springs another surprise! I assumed brain tissue and spinal cord tissue were the same and that the mechanisms causing tissue damage were the same. Are anti-CD20 therapies and BTK inhibitors having any impact on the mechanisms behind spinal cord atrophy? Are you suggesting that different therapies may be required to tackle tissue damage in the spinal cord?
They are somewhat the same, and they aren't... I know it's confusing. one of the biggest differences has to do with the mitochondria of the neurons, and the mitochondrial dysfunction is a big part of multiple sclerosis. This might help explain a little more:
Metabolic Differences:
Spinal cord mitochondria show lower rates of oxidative phosphorylation compared to brain mitochondria, potentially due to lower levels of respiratory complexes, according to a study published in the American Physiological Society Journal. They also accumulate less calcium and generate more reactive oxygen species (ROS) with certain substrates.
Vulnerability to Damage:
The differences in calcium handling and ROS production suggest spinal cord mitochondria may be more vulnerable to oxidative damage and calcium overload under certain conditions. This could contribute to the increased susceptibility of spinal cord motor neurons in conditions like amyotrophic lateral sclerosis (ALS).
Functional Distinctions:
The study also indicates that spinal cord mitochondria have lower Ca2+ accumulation capacity and generate more ROS than brain mitochondria, particularly when utilizing specific substrates.
Morphological Differences:
Research suggests that mitochondrial morphology can vary within neurons, with distinct shapes observed in dendrites and axons. During neural differentiation, mitochondria reshape from short and thick to thinner and elongated, forming a more complex network.
------------------------------------------------------------
Also important, although somewhat different, are the functions of the neurons and interneurons in the brain and spinal cord. While both the brain and spinal cord contain sensory and motor neurons, carrying the signals for sensory and motor functions are primarily the purview of the spinal cord, and the brain neurons control many functions at once other than just processing sensory information and sending out motor signals. The brain is the computer (CPU), and the spinal cord is all of the cables. And the constituent neurons reflect that. This last part I probably got some of it wrong, as I haven't been in school for a long time, and I wasn't the greatest student.
I’m in australia and I get brain and spinal cord in all my annual MRIs. Been doing that for 4 years now. Thankfully steady
The gd aspect does make me nervous however I’ve switched to non contrast now as things have settled down
The one thing I keep debating and good to get your view is tysabri > cladribine. I’m stable and doing really well on NTZ but the thought of going to cladribine whilst I’m JC negative and stable is appealing however I’m concerned about rebound activity and potentially doing worse by poking the bear. My neurologist is supportive of what I decide to do but it’s the million dollar question
Keep us updated please , I find myself in the same sort of situation.
I’m not sure if you can return to tysabri after cladribine if you relapse?
It’s the unknown that’s terrifying
All my visible lesions are in my spinal cord, my brain still shows now lesions in MRIs after 12 years of MS. Their shape doesn''t indicate NMOSD though and I've been negative for aquaporin-4-antibodies. Out of my four spinal cord lesions (three in C-spine, one in T-spine) only one was connected to a clear relapse - the others were either asymptomatic or mistaken for paroxysmal symptoms. I'm just saying this, because without spinal cord MRIs I'm not sure I'd even have an MS diagnosis and therefore access to DMTs to prevent further damage.
I have had both cladribine and kesimpta within a 4 years period. still got a new lesion so I am doing HSCT.
I am having trouble because I seem to have a neurologist who doesn't really care to stay completely on top of things. Every time I call with questions--which is pretty infrequently--he never seems to have the time to call me back, and I have to figure out things on my own. Recently as a couple of weeks ago my symptoms of muscle weakness, and contracture, have become markedly worse. But I have I don't know whether to understand this as a relapse, or just the normal course of progression. And my neurologist is really not helping in this regard.
I do understand that relapses are described as new symptoms or reawakened old symptoms that persist for 24 hours or more. But that leaves things open ended, as it doesn't explain the other side of me equation. I guess I'll show explain it this way: I understand the end result of a relapse definition as something that persists for 24 hours or more. But deciding whether something is a relapse or just worsening progression, how is that is decided from the way that symptoms present themselves? An example would be that my hands have been getting worse for some time now, but recently they got a lot worse, and I don't really notice that I have any new infections or something else that have possibly initiated this. So how can I tell which is which, to inform my next step? I have read somewhere that relapses can last anywhere from days to months. That does not bode well as whatever is causing something below the surface, it could be adding to ongoing damage that will be permanent. And worsening progression just come on suddenly, and just persist? Or does it come on slowly or very slowly? Or perhaps it vacillates back and forth between slow and quickly? This is all very concerning and really stressful.
I have never tried rituximab, but I have gone on mavenclad before. I wasn't able to continue the Mavenclad though for more than one year because of issues with chronic bladder infections. Like I said I never tried rituximab, but early in my disease my then neurologist decided to try cyclophosphamide Because she had done a ton of research trying to catch up with new ideas in MS research, as she was only a general neurologist and really didn't know very much about multiple sclerosis. This was in 2002. She was on to something, but this was still somewhat outlier type of thinking at the time. She also tried things like Cellcept to hopefully help me arrest the disease progression. Pretty forward thinking for someone who was somewhat out of their wheelhouse. You make very good points professor G: we need all the effective medications for multiple sclerosis, and pitting them against each other has no real value when the experiments are not designed well. The point that there are generic equivalents is especially salient since there are so many peole who are economically disadvantaged that need access to effective medications, and can't afford leading brand, high efficacy therapies.
Thanks Prof G, this was really useful. I've just had my first head MRI, 6 months after starting Siponimod. I hadn't considered that this would be a new baseline, and had wondered how my Neurologist would know when any new lesions occurred, especially given that it took 15 months from my previous MRI to actually start the medication. It now makes perfect sense!
I've never had an MRI with contrast. Is that the same as Gd? Theyve all just been the MRI process, originally of head,, then head and C-spine, then head and whole spine. My baseline at the new hospital in September 2023 was head and whole spine, but I knew going forward that it would just be head. I assumed this was just a different policy to the previous hospital, but there would appear to be a need to research whether whole spine MRI is useful and therefore necessary.
A lot of motor function disability comes from the lower motor neurons (i.e. the spine}.
Totally agree
Hi Prof Giovannoni and thank you for the nice article!
Is it true for cladribine that if you don't have relapses at the fourth year, like today have taken the first course in September 2021, it is less likely that the drug will fail you within a window of 10 years?
ProfG, would love to read a deep dive on Gd for monitoring... My neuro still insists on it, personally I have a fair bit of skepticism. I think part of the reasoning is that if one could catch an active lesion, there would be a discussion to be had that ocr failed (but I am not too sure it's helping all that much to begin with).
It'd be interesting to know in which part of the spinal cord were detected those lesions (not causing relapses), if it's mostly C spine or other parts as well. At least in our country they mostly include C spine along with brain when doing regular monitoring and study I was participating in also had included C spine.
perhaps this is why HSCT seems to be more effective for spinal lesions? what do you think?
I think there was an attack ms trial going on where as soon as people were diagnosed with ms they were put straight on tysabri as I believe it’s one of the fastest acting dmts ?
so mri from diagnosis and the new baseline say 6months later should hopefully show no new lesions would that not be the best option for those newly diagnosed if jcv - then transition to another dmt such as cladribine to give the best chance of controlling new lesions from the start ?
Also do patients always have to wait for cladribine to fail them before being offered another dmt?
could they start one of the lower efficacy dmts with lower associated risks say tecfidera to keep the monsters at bay say 2 years after completion on cladribine? Apologies if I’ve gone of course
y