A colleague suggested to me that the whole academic neurology community has imbibed too much anti-CD20 Kool-Aid and it is time for us to sober up. Is she is right?
Not really. They inhibit B cells. Their one advantage is that they are non depleting and hence reverse quite quickly. The latter may come with the risk of rebound.
To follow up on the risk of rebound I noticed you said "may" ... I'm surmising it's too soon to say but I'm wondering when the rebound effect was discoved with those S1P modulators you discussed. For someone (like me) who is in investigating participating in a BTK trial, I'm very interested in finding out all I can about rebound effect (or other concerns) before joining a trial for a new class of drug.
I stayed off ofatumumab in the US, at my own choosing, for 4 months, and walked into a pharmacy to get a yet unapproved by the FDA third dose of the Pfizer vaccine before resuming. Tests showed that the third dose boosted my antibody levels from low to the normal high levels. But I now intend to take my ofatumumab dose every 12 weeks instead of every month, for two reasons: because I think the monthly dose is too aggressive for my personal needs, and because I worry about the long term.
I don't want to be immunosuppressed at such a time, but I don't like the potential side effects in the other choices. BTK inhibitors sounded promising, but sounds like you're not so sure.
And I'm also wondering how getting back on ofatumumab will undo my immunity to COVID-19. I'm hoping the stretched out dose will help me retain immunity, but I am also considering getting a fourth dose in a few months when the time comes for me to get the finally approved booster.
Plasma cells that are the factories that make antibodies don't express CD20 on their surface and hence will continue to make antibodies despite treatment with an anti-CD20. However, although they are long-lived they don't live forever and need to be replenished in the future and this is where the problem lies. The cells the replenish plasma cells are the long-lived memory B-cells and these cells are taken out by anti-CD20 and anti-CD19 therapies. This is why I have concerns about indefinite treatment with anti-CD20. At some stage these treatments will need to be derisked.
I have the same concerns and questions about other vaccinations. I got vaccinated for Hep B and the shingles before starting on ofatumumab. In normal cases I think these would require a boost. With immunosuppressed pwMS, I suspect that boost might be required sooner, but do we have data?
My MS, though annoying, is not debilitating. My feet buzz, my legs feel it, and I have MS Hugs, but although I am not active in my work (as a software developer), I ride 20 miles on a weekly, somewhat hilly, bicycle ride. So surely I can modulate my therapy or find future windows within which I replenish my immunity.
I chose to delay my dose of ocrelizumab last year even though there was no evidence at that stage. I ended up with my vaccines 9 months after my ocrelizumab. I was then tested for antibodies (I paid for the spike protein test) and was confirmed to have a strong positive response.
I then had my next dose of ocrelizumab which was 4 months ago now. I intend to decline my next infusion and wait for my booster vaccine.
I am ‘lucky’ that I have a normal EDSS and my MS has not been active at all during this delaying (in terms of relapse). Given the time again I would make the same choices.
Thanks, informative post as ever. What about those of us about to start on ocr? With the NHS eligibility criteria the only option is to go on a less effective dmts like tec. There are no great options, how would you balance these making the choice? Other risk factors, age, comorbidities must feature in the equation as well?
I would suggest getting vaccinated first before starting ocrelizumab. The issue of having only anti-CD20 available first-line is an issue and needs to be addressed by the MS community in the UK. I really don't see a reason why we can't use natalizumab, alemtuzumab and cladribine first-line. This problem does not arise in such common-sense countries as Australia.
It looks as if there is good T-cell memory. However, the B-cell memory is poor. Even if people on anti-CD20 therapy make an antibody response it tends to be low titre, which is a predictor of the rapid waning of antibodies. The latter suggests long-lived memory plasma cells are not being formed and most of the antibodies are likely to be due to plasmablasts and short-lived plasma cells.
Yes, you are also correct in assuming that when you hit the person with another course of anti-CD20 these newly formed memory B--cells are likely to be extinguished. Unless there is a population that doesn't express CD20. I have hypothesised in the past these anti-CD20 negative B-cells must exist in long-term treated anti-CD20 patients.
am a 38 year old mum of two young children in school , been taking ocreluzimab for 2years and recently been informed I had no antibody response to Pfizer vaccines. This is a complete constant minefield of worry. The treatment has worked really well for me which I needed as my MS was very active and significantly impacting my life and career but now Covid is continuing to have a huge impact. I had high levels of JC virus when previously tested and was concerned about side effects of tec given my job are there a my other options and how risky is not having antibodies? I was hoping a T cell response may be enough but the new suggestion that it is antibodies you need causes me great concern. I am taking lots of precautions but with children in school i see it as only a matter of time before I catch Covid despite my best efforts to stay safe thank you
The solution is to miss a dose of ocrelizumab and have the booster when you have a few B-cells around. The chances of your MS disease activity coming back is very low.
I'm glad to read your conclusion about neurologists having to adress the issue of long-term immunosuppression. That's exactly what I have been trying to tell my neurologists after serious viral infections I had in 2019. Alas, a little too soon, and the wrong virus;)
I seriously hope
a) the issue will be taken seriously, even if covid would vanishes quickly
b) the attention will not be limited to specific DMTs and/or (specific) viral infections
In my experience, many neurologists have a very limited understanding of immunological implications of the DMTs they prescribe, and just follow general guidelines.
So yes, I fully endorse your conclusions!
And maybe it's time for more cooperation with immunologists?
Hi Prof Giovannoni, thank you for your newsletter and the effort you're putting in to make a positive difference around the world. I'm about to start Kesimpta in 3 weeks (4 weeks after my second Pfizer shot). I see this is the recommended time-frame from many governments around the world, but I wonder about your thoughts on this. Do most people get enough of an immune response within 4 weeks to start anti-CD20 therapy?
I saw in one of your other comments that the real issue may be long-term with memory B-cell depletion, so maybe that's where the most concern should lie? If so, do you have any predictions about how long most people would need to be on an anti-CD20 treatment before they would run into problems, even if they were lucky enough to have a robust immune response to a COVID vaccines originally?
Yes, being vaccinated before starting an anti-CD20 therapy and waiting 3-4 weeks to make sure your immune system has a chance to make antibodies and T-cell responses is ideal. Whether this sort of vaccine immune memory will be shortened is a moot point. The reason U say this is that booster vaccine responses on anti-CD20 are blunted as well.
I picked up on CD20 research early on from Europe, and it was yet another reason from many to choose Cladribine. I need to research the efficacy of mixing vaccines to see which work best as a hybrid approach. There are many more proteins of the virus which are detected by the immune system as part of natural immunity(29?) rather than the 1 spike protein trained by the pfizer vaccine. Lets see what some immunologist ms specialists say..
I can sort of speak from experience: I had a third vaccination (booster) recently, and I am trying to get tested to see if there is a response. Also through a series of mishaps due to residing in a nursing facility, I haven’t received an ocrelizumab infusion since June of 2020. My next infusion would have been December 2020, but fortunately my neurologist is really on top of things and told me to get vaccinated first. It took three months to get vaccinated (the corporate nursing facilities here are lousy), which was March of this year. So now it would have been June of this year for my next Ocrevus infusion, but I heard about all the confusion around anti-CD20 therapies and asked my neurologist if I should get a booster first… he said yes, good idea. Again the facility was consistent in letting everyone down, and I finally had my booster shot two weeks ago. So now I’m scheduled for my Ocrevus infusion in December—18 months after my last infusion. Unfortunately in the meantime I have suffered four UTIs, with three severe enough to put me in the hospital… and I’m in an acute care nursing facility!
Thanks for writing an objective assessment. In the US, it feels like neurologists are stuck on their original theory - "timing the vaccines will help, and you don't need a robust b-cell response to defeat covid because of t-cells." That theory hasn't held up to the evidence so far. I was fully vaccinated before my first-ever Ocrevus treatment. Should react ok to the booster, but as of now I'm not planning to get the next scheduled O dose in November. I'm going to discuss with my doc whether I should delay Ocrevus or switch. It sucks that we have to prepare for endemic covid, but at least there are good options for MS treatment.
It is quite clear that navigating this space is quite daunting for pwMS and their HCPs. However, as data emerges things get easier. The problem is with uncertainty and not having data to make informed decisions.
Informing people about the situation the risks and advantages is what can be done. The team that follows me is perfectly aware of everything. I feel they prefer to go for ocrelizumab infusion but they listen to their patients that are delaying like me. Should the neurologists advise be tuned based on comorbidities ie advise to wait for those at greater risk? Also effectively vaccinating immunosuppressed people will prevent them to become a mutation place for covid
Can I please check that following alemtuzumab that B cells and T cells do reconstitute
Also is there a way to check whether vaccinations have worked on you or whether you belong to the percentage of people upon whom the vaccination has no effect?
If that were the case surely having another vaccination is pointless or perhaps an alternative covid vaccination working in a different way would be a better idea for a booster
Yes, post alemtuzumab both the T-cells and B-cells reconstitute to a level that allows very good vaccine responses and peripheral immune surveillance. B-cells tend to overshoot their baseline by about 50% and T-cells don't get back to baseline but are usually in the normal range. In a minority of people, the T-cells remain below the lower limit of normal, usually at a grade 1 level of lymphopaenia (800-1,000/mm3).
Yes and no. Passive immunisation is not only expensive but will be a logistical nightmare. Who will get the antibodies? I suspect the NHS will eventually allow this as a treatment for very vulnerable people who get COVID-19. I think the solution will come when we get effective small-molecule antiviral agents against SARS-CoV-2. However, these will be virus-specific so what do with all the other emerging viral infections.
America’s Centres for Disease Control and Prevention released a study showing that Moderna’s covid-19 vaccine was 95% effective at preventing hospitalisation, compared with 80% for Pfizer-BioNTech’s and 60% for Johnson & Johnson’s. A separate study demonstrated that unvaccinated people were 11 times more likely to die of the disease than those who were fully jabbed.
Will BTK inhibitors address some of these challenges?
Not really. They inhibit B cells. Their one advantage is that they are non depleting and hence reverse quite quickly. The latter may come with the risk of rebound.
To follow up on the risk of rebound I noticed you said "may" ... I'm surmising it's too soon to say but I'm wondering when the rebound effect was discoved with those S1P modulators you discussed. For someone (like me) who is in investigating participating in a BTK trial, I'm very interested in finding out all I can about rebound effect (or other concerns) before joining a trial for a new class of drug.
I stayed off ofatumumab in the US, at my own choosing, for 4 months, and walked into a pharmacy to get a yet unapproved by the FDA third dose of the Pfizer vaccine before resuming. Tests showed that the third dose boosted my antibody levels from low to the normal high levels. But I now intend to take my ofatumumab dose every 12 weeks instead of every month, for two reasons: because I think the monthly dose is too aggressive for my personal needs, and because I worry about the long term.
I don't want to be immunosuppressed at such a time, but I don't like the potential side effects in the other choices. BTK inhibitors sounded promising, but sounds like you're not so sure.
And I'm also wondering how getting back on ofatumumab will undo my immunity to COVID-19. I'm hoping the stretched out dose will help me retain immunity, but I am also considering getting a fourth dose in a few months when the time comes for me to get the finally approved booster.
Plasma cells that are the factories that make antibodies don't express CD20 on their surface and hence will continue to make antibodies despite treatment with an anti-CD20. However, although they are long-lived they don't live forever and need to be replenished in the future and this is where the problem lies. The cells the replenish plasma cells are the long-lived memory B-cells and these cells are taken out by anti-CD20 and anti-CD19 therapies. This is why I have concerns about indefinite treatment with anti-CD20. At some stage these treatments will need to be derisked.
I have the same concerns and questions about other vaccinations. I got vaccinated for Hep B and the shingles before starting on ofatumumab. In normal cases I think these would require a boost. With immunosuppressed pwMS, I suspect that boost might be required sooner, but do we have data?
My MS, though annoying, is not debilitating. My feet buzz, my legs feel it, and I have MS Hugs, but although I am not active in my work (as a software developer), I ride 20 miles on a weekly, somewhat hilly, bicycle ride. So surely I can modulate my therapy or find future windows within which I replenish my immunity.
Give patients the choice.
I chose to delay my dose of ocrelizumab last year even though there was no evidence at that stage. I ended up with my vaccines 9 months after my ocrelizumab. I was then tested for antibodies (I paid for the spike protein test) and was confirmed to have a strong positive response.
I then had my next dose of ocrelizumab which was 4 months ago now. I intend to decline my next infusion and wait for my booster vaccine.
I am ‘lucky’ that I have a normal EDSS and my MS has not been active at all during this delaying (in terms of relapse). Given the time again I would make the same choices.
Good luck to everyone navigating this mess.
I also forgot to say that I think ocrelizumab lasts longer than 6 months and is probably over-dosed anyway, which helped make my decision last year
Not sure it overdosed; I think it may actually be underdosed in terms of targeting smouldering MS mechanisms.
Thanks, informative post as ever. What about those of us about to start on ocr? With the NHS eligibility criteria the only option is to go on a less effective dmts like tec. There are no great options, how would you balance these making the choice? Other risk factors, age, comorbidities must feature in the equation as well?
I would suggest getting vaccinated first before starting ocrelizumab. The issue of having only anti-CD20 available first-line is an issue and needs to be addressed by the MS community in the UK. I really don't see a reason why we can't use natalizumab, alemtuzumab and cladribine first-line. This problem does not arise in such common-sense countries as Australia.
glad to be an Aussie :D
How do you pose a query to the substack?
My queries:
Do patients on Anti-CD20 or Fingolimod mount a durable immune memory to SARS-Co-2 disease while on treatment?
For patients using Rituximab long term do they have a better chance to create memory cells closer to (or slightly past) their 6 month reinfusion date?
Much appreciated,
Felicity
It looks as if there is good T-cell memory. However, the B-cell memory is poor. Even if people on anti-CD20 therapy make an antibody response it tends to be low titre, which is a predictor of the rapid waning of antibodies. The latter suggests long-lived memory plasma cells are not being formed and most of the antibodies are likely to be due to plasmablasts and short-lived plasma cells.
Yes, you are also correct in assuming that when you hit the person with another course of anti-CD20 these newly formed memory B--cells are likely to be extinguished. Unless there is a population that doesn't express CD20. I have hypothesised in the past these anti-CD20 negative B-cells must exist in long-term treated anti-CD20 patients.
am a 38 year old mum of two young children in school , been taking ocreluzimab for 2years and recently been informed I had no antibody response to Pfizer vaccines. This is a complete constant minefield of worry. The treatment has worked really well for me which I needed as my MS was very active and significantly impacting my life and career but now Covid is continuing to have a huge impact. I had high levels of JC virus when previously tested and was concerned about side effects of tec given my job are there a my other options and how risky is not having antibodies? I was hoping a T cell response may be enough but the new suggestion that it is antibodies you need causes me great concern. I am taking lots of precautions but with children in school i see it as only a matter of time before I catch Covid despite my best efforts to stay safe thank you
The solution is to miss a dose of ocrelizumab and have the booster when you have a few B-cells around. The chances of your MS disease activity coming back is very low.
Thank you so much for taking the time to reply -it is much appreciated and will definitely discuss this with my neurologist
Australia patient : I’ve been on Ocrevus for 4 years , this scares me . What it be safe for me to swap to Cladribine or lemtrada?
Thanks
Yes, it would be safe, but this is something that takes time. Please see the following Newsletter:
https://gavingiovannoni.substack.com/p/switching-from-an-anti-cd20-the-why
I'm glad to read your conclusion about neurologists having to adress the issue of long-term immunosuppression. That's exactly what I have been trying to tell my neurologists after serious viral infections I had in 2019. Alas, a little too soon, and the wrong virus;)
I seriously hope
a) the issue will be taken seriously, even if covid would vanishes quickly
b) the attention will not be limited to specific DMTs and/or (specific) viral infections
In my experience, many neurologists have a very limited understanding of immunological implications of the DMTs they prescribe, and just follow general guidelines.
So yes, I fully endorse your conclusions!
And maybe it's time for more cooperation with immunologists?
If neurologists are prepared to prescribe immunotherapies they are obliged to know about how they work and how to manage the associated complications.
More profound knowledge of how they work is a first important step.
No need to rush into managing the complications...
Hi Prof Giovannoni, thank you for your newsletter and the effort you're putting in to make a positive difference around the world. I'm about to start Kesimpta in 3 weeks (4 weeks after my second Pfizer shot). I see this is the recommended time-frame from many governments around the world, but I wonder about your thoughts on this. Do most people get enough of an immune response within 4 weeks to start anti-CD20 therapy?
I saw in one of your other comments that the real issue may be long-term with memory B-cell depletion, so maybe that's where the most concern should lie? If so, do you have any predictions about how long most people would need to be on an anti-CD20 treatment before they would run into problems, even if they were lucky enough to have a robust immune response to a COVID vaccines originally?
Thank you again for all you're doing!
Yes, being vaccinated before starting an anti-CD20 therapy and waiting 3-4 weeks to make sure your immune system has a chance to make antibodies and T-cell responses is ideal. Whether this sort of vaccine immune memory will be shortened is a moot point. The reason U say this is that booster vaccine responses on anti-CD20 are blunted as well.
I picked up on CD20 research early on from Europe, and it was yet another reason from many to choose Cladribine. I need to research the efficacy of mixing vaccines to see which work best as a hybrid approach. There are many more proteins of the virus which are detected by the immune system as part of natural immunity(29?) rather than the 1 spike protein trained by the pfizer vaccine. Lets see what some immunologist ms specialists say..
I can sort of speak from experience: I had a third vaccination (booster) recently, and I am trying to get tested to see if there is a response. Also through a series of mishaps due to residing in a nursing facility, I haven’t received an ocrelizumab infusion since June of 2020. My next infusion would have been December 2020, but fortunately my neurologist is really on top of things and told me to get vaccinated first. It took three months to get vaccinated (the corporate nursing facilities here are lousy), which was March of this year. So now it would have been June of this year for my next Ocrevus infusion, but I heard about all the confusion around anti-CD20 therapies and asked my neurologist if I should get a booster first… he said yes, good idea. Again the facility was consistent in letting everyone down, and I finally had my booster shot two weeks ago. So now I’m scheduled for my Ocrevus infusion in December—18 months after my last infusion. Unfortunately in the meantime I have suffered four UTIs, with three severe enough to put me in the hospital… and I’m in an acute care nursing facility!
Thanks for writing an objective assessment. In the US, it feels like neurologists are stuck on their original theory - "timing the vaccines will help, and you don't need a robust b-cell response to defeat covid because of t-cells." That theory hasn't held up to the evidence so far. I was fully vaccinated before my first-ever Ocrevus treatment. Should react ok to the booster, but as of now I'm not planning to get the next scheduled O dose in November. I'm going to discuss with my doc whether I should delay Ocrevus or switch. It sucks that we have to prepare for endemic covid, but at least there are good options for MS treatment.
It is quite clear that navigating this space is quite daunting for pwMS and their HCPs. However, as data emerges things get easier. The problem is with uncertainty and not having data to make informed decisions.
Informing people about the situation the risks and advantages is what can be done. The team that follows me is perfectly aware of everything. I feel they prefer to go for ocrelizumab infusion but they listen to their patients that are delaying like me. Should the neurologists advise be tuned based on comorbidities ie advise to wait for those at greater risk? Also effectively vaccinating immunosuppressed people will prevent them to become a mutation place for covid
Can I please check that following alemtuzumab that B cells and T cells do reconstitute
Also is there a way to check whether vaccinations have worked on you or whether you belong to the percentage of people upon whom the vaccination has no effect?
If that were the case surely having another vaccination is pointless or perhaps an alternative covid vaccination working in a different way would be a better idea for a booster
Yes, post alemtuzumab both the T-cells and B-cells reconstitute to a level that allows very good vaccine responses and peripheral immune surveillance. B-cells tend to overshoot their baseline by about 50% and T-cells don't get back to baseline but are usually in the normal range. In a minority of people, the T-cells remain below the lower limit of normal, usually at a grade 1 level of lymphopaenia (800-1,000/mm3).
Isn't passive immunization the obvious solution?
Yes and no. Passive immunisation is not only expensive but will be a logistical nightmare. Who will get the antibodies? I suspect the NHS will eventually allow this as a treatment for very vulnerable people who get COVID-19. I think the solution will come when we get effective small-molecule antiviral agents against SARS-CoV-2. However, these will be virus-specific so what do with all the other emerging viral infections.
I think it would heavily depend on the pricing for something like azd7442. It's not like hospitalization of patients is an affordable option, either.
America’s Centres for Disease Control and Prevention released a study showing that Moderna’s covid-19 vaccine was 95% effective at preventing hospitalisation, compared with 80% for Pfizer-BioNTech’s and 60% for Johnson & Johnson’s. A separate study demonstrated that unvaccinated people were 11 times more likely to die of the disease than those who were fully jabbed.
The take-home message is that Moderna's vaccine has the edge over the other vaccines in terms of inducing a robust protective immunity.