The other interesting thing with Tysabri is how many people really love it compared to B cell depleters etc
Trauling thru Facebook / social media so many patients on Tysabri rave about it and even when switching to other DMTs. But I don't see the same in Ocrevus groups or others...wonder why that is?
Many thanks for your explanations and rationale - they provide me with greater understanding of the situation I find myself in and help give me confidence that I'm making the best possible choice of new medication. Much appreciation for you taking the time to reply - it makes so much difference!
Thanks for such a timely and detailed summary of the use of Natalizumab. I have been on natalizumab for nearly 5 years of which half that time has been on EID ( 6 weekly infusions). All has been great until I seroconverted to JCV positive on my last test in May22. Antibody levels were particularly high at this point (2.9) but a second test last month was slightly lower (2.6). A change is of course on the cards as a result. I clearly prefer to switch to an immune reconstitution therapy ( Cladribine) due to the shorter term immuno suppression rather than continuous as with ant-CD20 therapies ( Kesimpta and Ocrevius are the other options).
However I have concerns regarding any possibility of PML emerging when the immune system is reduced on either therapy but particularly for Cladribine as, although shorter term it is irreversible. I'd be grateful for your thoughts on what factors to consider in this imminent choice ( latest MRI is stable and no sign of PML or other activity) , bloods and vaccinations (HPV and Shingles have been completed) and Smear test is clear so it appears I'm good to go except for waiting for the lumbar puncture test for JCV DNA in the CSF. If this is clear does it suggest that Cladribine is on the cards as the next DMT? What else should I be considering in making my decision? I am 63 and have been diagnosed for 11 years, NEIDA on natalizumab for 5years but had a number of meds fairly short term before that ( Tecfidera, Avonex, Gilenya). All had to stop due to side effects not ineffectiveness. Had rebound after Gilenya withdrawal , which caused my last relapse in 2017.
In general cladribine is an ideal treatment for older people with MS, i.e. >55 years. Why? This is the age when immune senescence starts to interact with chronic long term immunosuppression and your risk of serious infections and possible secondary malignancy increase. Cladribine is ideal, because it is an IRT (immune reconstitution therapy) that does not leave you chronically immunosuppressed and put the majority of people into remission (NEIDA).
Regarding PML risk: when somebody goes from being JCV negative to positive with a high index it indicates they have been recently infected with the virus. However., the risk of PML remains low for the next 6-12 months and probably up to 2 years. This is because one is likely to have been infected with a wild-type JCV strain, i.e. one that does not cause PML. The virus that causes PML has to mutate and acquire the ability to infect glial cells in the CNS. The latter process takes many months or even years to occur as it involves many mutations to be selected. This is why the risk of carry-over PML when switching from natalizumab to cladribine or another IRT (AHSCT. alemtuzumab) is very very low, i.e. you are switching when the chance of having a mutant strain of JCV is low.
So in theory if you are testing every 3 months for JC levels (like me) and that test eventually comes back positive, switching to Cladrabine immediately should have a very low risk of PML (pending MRIs) if you do that asap?
There is really no reason to test JCV serology every 3 months. This is not good use of resources. Every 6 months is fine.
Yes, if you seroconvert it means you were infected with the virus in the last 6 months, or in your case the last 3 months. As it takes longer than 6 months, i.e. it probably takes at lease 12 months and more likely years, for the wild type virus to mutate to become virulent. Therefore it is safe to switch to an IRT without worrying about carry-over PML if you do it early within 6 months of becoming positive. Saying this I still do a baseline switching MRI to have it as a reference and don't do an LP for CSF JCV-DNA analysis in this situation.
As someone on Tysabri the PML risk is my biggest worry (at this stage I'm JC negative and test myself every 3 months)
I've always thought to switch whilst I am JC negative as it makes the most rational sense and lowers risk of PML however with all my recent MRIs showing NEDA / stable no new lesions no new symptoms it becomes harder to change with the uncertainty of what happens
I wish there was a treatment for PML. It would make all of us have a lot more confidence and relieve a tonne of anxiety!
Thanks so much for this. May I ask why some HSCT centres insist on a 3 month washout period of Tysabri before beginning treatment? What could someone do during those 3 months to try and reduce the chance of rebound activity before the HSCT process begins?
Thanks! Any advice on how to best get through the washout period without relapsing? Administration of IVMP?
Any experience or advice you have on this would be appreciated as my wife has failed Tysabri and is now looking at HSCT. Just worried an aggressive rebound happens before the 3 months are up.
Thank you so much for writing these newsletters. They are so educational and informative and an amazing contribution to the MS patients and caregivers community. I am reading each newsletter enthusiastically and they are not too detailed. Please continue… cannot stress enough how helpful it is
Thank you, excellent overview. Are there any studies that compare the efficacy of Ocrevus to Tysabri, radiographically, or clinically related to disability levels?
Does a switch between the two high efficacy DMTs result in measurable changes in progression in terms of lesion load or clinical progression in terms of EDSS? A statistically significant difference. What is your experience anecdotally?
Do dome people do better on one drug vs the other on these metrics? Not accounting for differences with concerns with PML and other side effects?
Another example of an anti-CD20 beating teriflunomide on relapses, MRI activity and NEIDA, but not on disability progression or brain volume loss. This is telling us that anti-CD20 therapy, or peripheral B-cell depletion, is very good at switching off focal inflammatory lesions, but not targeting the real MS or smouldering disease. A potential reason is these monoclonal antibodies don't get into the CNS in high enough concentrations to deplete CNS B-cells.
We really need to go beyond NEIDA and focus on the end-organ. The questions you need to ask is what is happening to my brain volume and brain reserve? Will get to old age with enough brain reserve to age normally?
Please note I have written on this topic many times on MS-Selfie. Do you want me to do another post on the topic?
Am I to understand then if you have more advanced progressive MS you probably have more smoldering lesions? Therefore anti-cd 20 therapies that target focal inflammatory lesions probably won’t be as helpful?
When it comes to NEIDA (relapses and MRI activity) the anti-CD20 therapies are top of the pops. However, when you go beyond NEIDA and look at the impact on slowing disability worsening, sustained disability improvement rates and slowing brain volume loss I would give natalizumab the edge. And above natalizumab are alemtuzumab and AHSCT. What is remarkable about natalizumab is the rapid onset of action and its anti-fatigue effects; in my experience you don't see this with anti_CD20 therapies.
The CLASSIC follow-up of the CLARITY & CLARITY extension (>10 years since last dose of cladribine) demonstrates that 56% hadn't required another DMT and overall the EDSS had only increased on average by 0.5-1.0. So very good.
Regarding brain volume loss in the CLARITY study it was over 0.5% per annum compared to ~0.15% pa in the ORACLE (CIS study). The difference could be explained by age and disease duration much greater in CLARITY compared to ORACLE. The message is loud and clear if you treat MS early with cladribine you will do so much better than delayed access (~8 years in CLARITY). Great pity we can't use cladribine early in MS, i.e. first line.
I’ve got a general question - in the context of how you define ‘years with ms’ do you count from an isolated CIS or when you become eligible for diagnosis using MacDonald criteria?
I had CIS but nothing further for 4 years. So a significant gap… do I count my years with MS since CIS or diagnosis? Thanks.
Both. But the most important one is time since symptom onset. Time since diagnosis is flaky and subject to many extraneous factors; e.g. healthcare system delays.
Do you think once the EID efficacy results become better known and the real world evidence grows, there will be a notable uptick in natalizumab use? it would seem like it to me but I don't really know what makes things like that shift.
Yes and no. What we really need is to have broader access to natalizumab, i.e. a first-line label for active MS rather than it being pigeon-holed into the RES (rapidly-evolving severe) bracket.
Well, that is at least one problem that we don't have in the US, home of the most expensive terrible outcomes in the developed world. I actually met a woman at an MS meetup once who was being treated using the "tysabri first, ask questions later" method for newly diagnosed folks that you're pushing for.
Could Tysabri worsen other non MS demyelinating diseases/ symptoms like MOG? Have you ever had patients develop worsening symptoms on Tysabri with no evidence of new disease activity?
There is a literature on this; mainly case studies or small series. I think this is reporting bias and the cases it doesn't make worse don't get reported. I can't think of a reason, from a biological perspective, why natalizumab would make antibody mediated CNS disease like anti-MOG mediated CNS demyelination worse.
I have seen a few pwMS fail natalizumab with severe disease and most of them had ADAs (anti-drug antibodies), which neutralise natalizumab's activity.
What do you think about this research regarding natalizumab worsening symptoms in MOG patients when initially used for suspected MS?
“ Patients with MOGAD treated with MS disease modifying therapies are known to relapse as was found in this case series and also reported previously [22]. Natalizumab is a monoclonal antibody against the α4β1 integrin and reduces the entry of CD4+ and CD8+ T lymphocytes into the CNS and has been shown to be quite effective in the treatment of relapsing remitting MS [23]. By virtue of its mechanism of action natalizumab can increase total peripheral lymphocyte counts, and it has also been shown to increase CD138+ plasma cells and immature CD19+CD10+ pre-B cells in the peripheral blood of natalizumab-treated patients [24]. Neuromyelitis optica spectrum disorder (NMOSD) and MOGAD are antibody mediated diseases and with increased CD138 + cells one could speculate increasing production of pathogenic antibodies, and therefore increased disease activity.”
Not sure it makes things worse; it just doesn't work in auto-antibody mediated diseases. The problem with the literature is reporting bias. Case that have activity on natalizumab get reported and those that don't get worse don't get reported. Natalizumab does not stop the passive transfer of autoantibodies across the BBB, but it does stop the trafficking of effector cells.
I suspect that too, but take it from your answer that the BIIB statisticians have not queried their post-marketing database (Touch?) to profile that risk as a function of treatment duration or discontinuation? Is that risk so low not to warrant the publication of accurate metrics?
Unfortunately on the NHS you have to stop natalizumab when you become a wheelchair user or reach EDSS 7.0. In addition natalizumab has never been shown to delay worsening in advanced MS. Saying this I have little doubt that it will be protecting upper limb function.
Thank you for this, Prof G. I'm grateful for your MS Selfies, and there couldn't be too many for me. I'm still prosessing your last few about gaslighting, which have been massive and amazing for me. Treatment-wise, I'm having my second course of Lemtrada soon, and keeping an open mind about after that. I don't think I ever had the option of Tysabri, but I would have chosen Lemtrada (or AHSCT) anyway.
The other interesting thing with Tysabri is how many people really love it compared to B cell depleters etc
Trauling thru Facebook / social media so many patients on Tysabri rave about it and even when switching to other DMTs. But I don't see the same in Ocrevus groups or others...wonder why that is?
Many thanks for your explanations and rationale - they provide me with greater understanding of the situation I find myself in and help give me confidence that I'm making the best possible choice of new medication. Much appreciation for you taking the time to reply - it makes so much difference!
Thanks for such a timely and detailed summary of the use of Natalizumab. I have been on natalizumab for nearly 5 years of which half that time has been on EID ( 6 weekly infusions). All has been great until I seroconverted to JCV positive on my last test in May22. Antibody levels were particularly high at this point (2.9) but a second test last month was slightly lower (2.6). A change is of course on the cards as a result. I clearly prefer to switch to an immune reconstitution therapy ( Cladribine) due to the shorter term immuno suppression rather than continuous as with ant-CD20 therapies ( Kesimpta and Ocrevius are the other options).
However I have concerns regarding any possibility of PML emerging when the immune system is reduced on either therapy but particularly for Cladribine as, although shorter term it is irreversible. I'd be grateful for your thoughts on what factors to consider in this imminent choice ( latest MRI is stable and no sign of PML or other activity) , bloods and vaccinations (HPV and Shingles have been completed) and Smear test is clear so it appears I'm good to go except for waiting for the lumbar puncture test for JCV DNA in the CSF. If this is clear does it suggest that Cladribine is on the cards as the next DMT? What else should I be considering in making my decision? I am 63 and have been diagnosed for 11 years, NEIDA on natalizumab for 5years but had a number of meds fairly short term before that ( Tecfidera, Avonex, Gilenya). All had to stop due to side effects not ineffectiveness. Had rebound after Gilenya withdrawal , which caused my last relapse in 2017.
Thanks so much!
In general cladribine is an ideal treatment for older people with MS, i.e. >55 years. Why? This is the age when immune senescence starts to interact with chronic long term immunosuppression and your risk of serious infections and possible secondary malignancy increase. Cladribine is ideal, because it is an IRT (immune reconstitution therapy) that does not leave you chronically immunosuppressed and put the majority of people into remission (NEIDA).
Regarding PML risk: when somebody goes from being JCV negative to positive with a high index it indicates they have been recently infected with the virus. However., the risk of PML remains low for the next 6-12 months and probably up to 2 years. This is because one is likely to have been infected with a wild-type JCV strain, i.e. one that does not cause PML. The virus that causes PML has to mutate and acquire the ability to infect glial cells in the CNS. The latter process takes many months or even years to occur as it involves many mutations to be selected. This is why the risk of carry-over PML when switching from natalizumab to cladribine or another IRT (AHSCT. alemtuzumab) is very very low, i.e. you are switching when the chance of having a mutant strain of JCV is low.
So in theory if you are testing every 3 months for JC levels (like me) and that test eventually comes back positive, switching to Cladrabine immediately should have a very low risk of PML (pending MRIs) if you do that asap?
There is really no reason to test JCV serology every 3 months. This is not good use of resources. Every 6 months is fine.
Yes, if you seroconvert it means you were infected with the virus in the last 6 months, or in your case the last 3 months. As it takes longer than 6 months, i.e. it probably takes at lease 12 months and more likely years, for the wild type virus to mutate to become virulent. Therefore it is safe to switch to an IRT without worrying about carry-over PML if you do it early within 6 months of becoming positive. Saying this I still do a baseline switching MRI to have it as a reference and don't do an LP for CSF JCV-DNA analysis in this situation.
Thank you.
To be honest I have anxiety hence the every 3 months which my neurologist agreed reluctantly.
Because our tests in Oz take about 4-5 weeks to come back due to going to Unilab in Denmark it allays my anxiety a bit knowing I'm testing regularly.
This is really great thank you
As someone on Tysabri the PML risk is my biggest worry (at this stage I'm JC negative and test myself every 3 months)
I've always thought to switch whilst I am JC negative as it makes the most rational sense and lowers risk of PML however with all my recent MRIs showing NEDA / stable no new lesions no new symptoms it becomes harder to change with the uncertainty of what happens
I wish there was a treatment for PML. It would make all of us have a lot more confidence and relieve a tonne of anxiety!
Thanks so much for this. May I ask why some HSCT centres insist on a 3 month washout period of Tysabri before beginning treatment? What could someone do during those 3 months to try and reduce the chance of rebound activity before the HSCT process begins?
Natalizumab affects the mobilisation of stem cells, which is why they want it out of the system.
Thanks! Any advice on how to best get through the washout period without relapsing? Administration of IVMP?
Any experience or advice you have on this would be appreciated as my wife has failed Tysabri and is now looking at HSCT. Just worried an aggressive rebound happens before the 3 months are up.
Thank you so much for writing these newsletters. They are so educational and informative and an amazing contribution to the MS patients and caregivers community. I am reading each newsletter enthusiastically and they are not too detailed. Please continue… cannot stress enough how helpful it is
At what point is it safe to restart tysabri after having hsct ? Im going to be asking to do this in october and got my cells back in march
Not sure I understand why you are going back onto natalizumab. Have you had breakthrough activity?
Ive worsened since having hsct, alot of the improvements i had on tysabri have dissapeared so im hoping to go on as maintenance
Thank you, excellent overview. Are there any studies that compare the efficacy of Ocrevus to Tysabri, radiographically, or clinically related to disability levels?
Does a switch between the two high efficacy DMTs result in measurable changes in progression in terms of lesion load or clinical progression in terms of EDSS? A statistically significant difference. What is your experience anecdotally?
Do dome people do better on one drug vs the other on these metrics? Not accounting for differences with concerns with PML and other side effects?
Have you seen this study?
Steinman et al. Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med 2022; 387:704-714. https://www.nejm.org/doi/full/10.1056/NEJMoa2201904
Another example of an anti-CD20 beating teriflunomide on relapses, MRI activity and NEIDA, but not on disability progression or brain volume loss. This is telling us that anti-CD20 therapy, or peripheral B-cell depletion, is very good at switching off focal inflammatory lesions, but not targeting the real MS or smouldering disease. A potential reason is these monoclonal antibodies don't get into the CNS in high enough concentrations to deplete CNS B-cells.
We really need to go beyond NEIDA and focus on the end-organ. The questions you need to ask is what is happening to my brain volume and brain reserve? Will get to old age with enough brain reserve to age normally?
Please note I have written on this topic many times on MS-Selfie. Do you want me to do another post on the topic?
I had not seen this study, thank you. I have read your posts regarding shouldering MS before, but I always welcome your writing on the topic.
Am I to understand then if you have more advanced progressive MS you probably have more smoldering lesions? Therefore anti-cd 20 therapies that target focal inflammatory lesions probably won’t be as helpful?
When it comes to NEIDA (relapses and MRI activity) the anti-CD20 therapies are top of the pops. However, when you go beyond NEIDA and look at the impact on slowing disability worsening, sustained disability improvement rates and slowing brain volume loss I would give natalizumab the edge. And above natalizumab are alemtuzumab and AHSCT. What is remarkable about natalizumab is the rapid onset of action and its anti-fatigue effects; in my experience you don't see this with anti_CD20 therapies.
Where does cladribine sit here? Too little data beyond CLARITY to say?
The CLASSIC follow-up of the CLARITY & CLARITY extension (>10 years since last dose of cladribine) demonstrates that 56% hadn't required another DMT and overall the EDSS had only increased on average by 0.5-1.0. So very good.
Regarding brain volume loss in the CLARITY study it was over 0.5% per annum compared to ~0.15% pa in the ORACLE (CIS study). The difference could be explained by age and disease duration much greater in CLARITY compared to ORACLE. The message is loud and clear if you treat MS early with cladribine you will do so much better than delayed access (~8 years in CLARITY). Great pity we can't use cladribine early in MS, i.e. first line.
I’ve got a general question - in the context of how you define ‘years with ms’ do you count from an isolated CIS or when you become eligible for diagnosis using MacDonald criteria?
I had CIS but nothing further for 4 years. So a significant gap… do I count my years with MS since CIS or diagnosis? Thanks.
Both. But the most important one is time since symptom onset. Time since diagnosis is flaky and subject to many extraneous factors; e.g. healthcare system delays.
Thanks for answering. It makes a big difference in my time-frame so it helps me with my decision making.
Do you think once the EID efficacy results become better known and the real world evidence grows, there will be a notable uptick in natalizumab use? it would seem like it to me but I don't really know what makes things like that shift.
Yes and no. What we really need is to have broader access to natalizumab, i.e. a first-line label for active MS rather than it being pigeon-holed into the RES (rapidly-evolving severe) bracket.
Well, that is at least one problem that we don't have in the US, home of the most expensive terrible outcomes in the developed world. I actually met a woman at an MS meetup once who was being treated using the "tysabri first, ask questions later" method for newly diagnosed folks that you're pushing for.
Could Tysabri worsen other non MS demyelinating diseases/ symptoms like MOG? Have you ever had patients develop worsening symptoms on Tysabri with no evidence of new disease activity?
There is a literature on this; mainly case studies or small series. I think this is reporting bias and the cases it doesn't make worse don't get reported. I can't think of a reason, from a biological perspective, why natalizumab would make antibody mediated CNS disease like anti-MOG mediated CNS demyelination worse.
I have seen a few pwMS fail natalizumab with severe disease and most of them had ADAs (anti-drug antibodies), which neutralise natalizumab's activity.
What do you think about this research regarding natalizumab worsening symptoms in MOG patients when initially used for suspected MS?
“ Patients with MOGAD treated with MS disease modifying therapies are known to relapse as was found in this case series and also reported previously [22]. Natalizumab is a monoclonal antibody against the α4β1 integrin and reduces the entry of CD4+ and CD8+ T lymphocytes into the CNS and has been shown to be quite effective in the treatment of relapsing remitting MS [23]. By virtue of its mechanism of action natalizumab can increase total peripheral lymphocyte counts, and it has also been shown to increase CD138+ plasma cells and immature CD19+CD10+ pre-B cells in the peripheral blood of natalizumab-treated patients [24]. Neuromyelitis optica spectrum disorder (NMOSD) and MOGAD are antibody mediated diseases and with increased CD138 + cells one could speculate increasing production of pathogenic antibodies, and therefore increased disease activity.”
https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-022-02612-6
We need a properly powered trial for a definitive trial, which is not going to happen
Not sure it makes things worse; it just doesn't work in auto-antibody mediated diseases. The problem with the literature is reporting bias. Case that have activity on natalizumab get reported and those that don't get worse don't get reported. Natalizumab does not stop the passive transfer of autoantibodies across the BBB, but it does stop the trafficking of effector cells.
Excellent article! Thank you Prof G.
Does the CNS Lymphoma malignancy risk compound after stopping Tysabri or would that risk revert back to the same level of tysabri-naive individuals?
I suspect it drops back towards normal as immune surveillance gets going again and the T & NK cells will hopefully find any rogue tumour cells.
On a positive note, it seems that the much awaited Grail galleri test can pick up a lymphoma DNA trace in the blood test: https://www.galleri.com/the-galleri-test/types-of-cancer-detected
I suspect that too, but take it from your answer that the BIIB statisticians have not queried their post-marketing database (Touch?) to profile that risk as a function of treatment duration or discontinuation? Is that risk so low not to warrant the publication of accurate metrics?
Thank you for all information you provide.
Do you recommend Natalizumab, for patients who are in wheelchairs? To possibly regain some of their function?
Thank you, for your continued support!
Unfortunately on the NHS you have to stop natalizumab when you become a wheelchair user or reach EDSS 7.0. In addition natalizumab has never been shown to delay worsening in advanced MS. Saying this I have little doubt that it will be protecting upper limb function.
Thank you for this
Thank you for this, Prof G. I'm grateful for your MS Selfies, and there couldn't be too many for me. I'm still prosessing your last few about gaslighting, which have been massive and amazing for me. Treatment-wise, I'm having my second course of Lemtrada soon, and keeping an open mind about after that. I don't think I ever had the option of Tysabri, but I would have chosen Lemtrada (or AHSCT) anyway.