This patient with active relapsing-remitting MS has been offered ocrelizumab or ofatumumab. Prof G discusses his views on these two DMTs and explains how to differentiate between the two.
I find the idea of ultimately passing the decision to her with the message of 'you choose' extremely problematic. I realise that when you are writing it all down it may not always convey nuances, so I comment with that in mind.
When you are diagnosed you are, to put it bluntly, in a complete shitstorm of emotion. New demands, fear, uncertainty doubt, general 'what-ifs' and it is appalling. Then to have the person who you'd like to be your rock regarding the medical stuff turn and tell you that the choice is all yours is something that, in the malestrom, you probably just accept.
Whatever the doctor thinks and however hard they work to minimise it, there is and always will be a power imbalance between patient and doctor. I recently discussed this at some length with a cardiologist friend, who is extremely experienced, but just caught a cancer diagnosis of their own. They were reflecting on what it was like to sit in front of the expert and just feel 'junior and scared' again. If it can happen to them then imagine a non-medic?
Trial aside: I would suggest that they want some sort of steer, even if you couch it in the six and two threes wrapper. They want to trust you.
After all, deep down, were you to have to make the choice for you or your close relative in her shoes then you'd know which way you'd go.
I am a grumpy old sod who has different views. I am trying to remark from the POV of three people I have spoken to recently. Their view is so very different. The main emotion is fear. It permeates everything else. Can you imagine the irrational fear that 'what if I chose the wrong one?' as well. As illogical as you may know that to be, for them it it is just another layer.
Best,
Dominic
PS: Nothing said about Covid vaccines etc going forward. I thought I heard murmurings about ofatumumab not having such a deleterious effect as ocrelizumab but feel on v shaky ground regarding this. Care to comment? Thank you
Very good point. One option I always add is for the patient to choose the option of you making the choice for them; i.e. paternalistic medicine.
To be honest I don't have enough information about this particular patient to say x or y. If I was seeing this patient myself, which I could do if I had a private practice, I would want to know a lot more about her life, job, plans for a family, etc.
I also need to know about her MS. She may be better off starting on DMF or oral cladribine rather than an anti-CD20. If her scan and CSF analysis shows she has very bad MS I would be guiding her towards alemtuzumab.
To be honest when it comes to head-2-head efficacy comparison in relation to an anti-inflammatory decision between ocrelizumab and ofatumumab the differences are not meaningful. I would give ocrelizumab the theoretical edge in terms of smouldering MS and I ofatumumab the edge on safety (it seems to be less immunosuppressive).
The vaccine data on ofatumumab is not available yet. Let's wait for that before making any claim that it is better than ocrelizumab.
Let’s say that this lady travelled a lot and may find a 6-monthly infusion difficult then self-administered ofatumumab would be the agent of choice. On the other hand if she was needle phobic in relation to injecting herself then ocrelizumab would be the recommendation. If she was diabetic it would be ofatumumab to avoid the need for steroids to prevent infusion reactions.
The point that needs to be made is that when deciding on a DMT for a patient it is the subtle things that make you decide on which DMT to recommend. Yes, I am sitting on the fence because I have to ;-)
“I also need to know about her MS. She may be better off starting on DMF or oral cladribine rather than an anti-CD20. If her scan and CSF analysis shows she has very bad MS I would be guiding her towards alemtuzumab.“
She is young and newly out of college. Her best option for convenience, future fertility planning and holding to “time is brain” would be IRT.
The trial gives her a shot at a possible IRT. This is well founded but she may get the comparator arm (or the trial may fail- although this seems unlikely).
Why not go with a definitive IRT? As a provider I would at least discuss these therapies with her- add them as options. Ultimately doctor and patient need to understand potential risks (doctor informs patient) and the motivation of the patient (is she conservative or aggressive in her approach to treatment).
I am thankful to hear your recommendation for the severest MS outlook is Alemtuzumab over oral Cladribine. This was the most insightful nugget of the entire case history for me.
Thank you for these long formats and detailed follow-ups.
Prof.....how can you steer this patient towards alemtuzumab based on CFS and MRI analysis? it is a second line agent. I'm asking for my own interest of course and slight frustration that some neurologists are not willing to apply the 'guidance' to suit patient choice
The guidelines are just that a guide. If the patient had an enhancing lesion, poor MRI and very high NFL levels and you were worried about her long-term prognosis you could potentially offer her alemtuzumab under exceptional circumstances. Medicine and neurology is not an algorithm, but an art and therefore you need to be flexible.
Thanks Prof. Sadly, not all neurologists think alike and will act like their hands are tied. Despite my own poor prognosis, i still received the NHS leaflet with the injectables 'circled' as my options. A lot of patients will not investigate any further and will miss out on potentially better outcomes as a result. Too many poor artists it seems
For US-based readers, insurance is a consideration. Typically, ocrelizumab goes through medical insurance because it is an infusion; ofatumumab goes through prescription insurance. I have found that my medical insurance is typically easier to deal with vs. prescription insurance - so not worrying about interruption in my medication delivery is a pro for Ocrevus. This may not be the same for others, but it is worth considering - albeit likely overwhelming, since most US patients don't know the difference between these two types of insurance...I have a Masters in Healthcare and still find it difficult to navigate.
Hi Dr. G., if you had a patient that had been on ocrelizumab for 5 years and paused for a year to improve vaccine response, would you have any preference when they restarted treatment between Ocrelizumab vs Ofatumumab? (Happy for quick thoughts or to submit as a case study if you prefer.)
Depends on whether or not you think ofatumumab is a low-dose anti-CD20 therapy and if you need CNS and deep tissue penetration or not. I suspect more ocrelizumab gets into the CNS than ofatumumab.
I'm back! Facing the same decision about whether to restart Ocrevus or switch to Kesimpta after a 10-month pause to hopefully get some antibodies from the bivalent Covid vaccine ahead of the holidays. (I am feeling very lucky that I repopulated into the normal levels of CD20 cells in just 10 months after 6+ years on the drug.)
Any new thinking on this topic? Given that I seem to repopulate B-cells quickly and Ocrevus is easier with my specific insurance plan, I'm inclined to stay on Ocrevus. I doubt that there will be another interesting vaccine for a while, so likely won't need to pause again.
[Side note - I hate Covid. I hate having to do daily math about my risk level based on scraps of data from cities far from where I live. I hate having to make big decisions about my MS treatments with major blind spots. I hate that most of my friends/family/co-workers have no qualms about being asymptomatic spreaders of a virus that made me sick for months over the summer. I hate that those same friends/family/co-workers also have no qualms about freely spreading their flu/RSV/bronchitis/other germs this season. I hate that rapid tests have turned out to not be a very good tool for me to have in-person interactions with other people. And I hate that it will be another 5ish months before the weather is good enough for outdoor socialization again.
If anyone has found a magical place with outdoor-friendly weather most of the year, that is serious about minimizing community levels of Covid and that lets people with MS emmigrate, please share!]
There is little to choose between ocrelizumab and ofatumamab in terms of peripheral B-cell depletion and anti-inflammatory effects. I think you get more CNS penetration with ocrelizumab and hence a possibly greater impact on CNS-resident B-cells and possibly end-organ damage.
OK, sounds good. Given that and the other factors important to me, it sounds like another year of Ocrevus is best plus some blood tests closer to the 6-month mark after doses to see how quickly I'm actually repopulating B-cells.
Hmm, I'm not sure how to weigh CNS/deep tissue penetration. Positive for OCB 14 years ago, so CNS involvement in the past (hasn't been tested since). CD19 back to 14% / 315 mm3 with 11 pause in Ocrelizumab. Seems like erring towards the potentially stronger option would make sense. As an added bonus, 2x/year infusions are easier to deal with insurance-wise than monthly shots (this bonus is specific to a particular US insurance plan, not all US insurance plans).
I hope you realise why it is so important for this patient to be enrolled in the high-dose ocrelizumab study. It is testing a hypothesis that I put forward 20+ years ago when I was doing my PhD that CNS resident B-cells and plasma cells are important drivers of progressive or smouldering MS pathology.
If high-dose ocrelizumab is confirmed to be more effective than standard-dose ocrelizumab then there is little doubt about what the choice of anti-CD20 will be in this patient and it will increase the race for CNS penetrant DMTs that target intrathecal B and plasma cells.
I would give the high-dose studies an over the odds (>50%) chance of being positive; my optimism is based on biology and is why we are doing the SIZOMUS trial.
One of the distinct advantages of any MS treatment is the ability to reduce the need for hospital attendences. If you live in a rural/remote area then the opportunity to give injections in the home is a huge advantage; it saves on travel costs, time and also accessibility to hospitals during poor weather. It frees up staff to provide satellite clinics in more rural areas which is a much better use of resources.
Dear sir, your newsletters provide us patients great insights into the disease and its treatment. You said you would want her to be on oral cladribine or alemtuzumab rather, if her MRI reveals enhancing lesions and CSF examination reveals raised nfl levels, and end organ damage/ brain volume loss should not be considered here as we are not comparing anti CD to other high efficacy treatments.
Could you please explain what therapies you refer to when you say high efficacy treatments.
Does oral cladribine also fall into that category of high efficacy DMDs and do you consider it to be better than anti CD20 therapies in terms of preserving brain and spine volume?
Apologies, for the confusion. With the information, she gave me I interpreted her case as being active MS and not highly active or rapidly evolving severe MS. Based on this she would be eligible for cladribine, alemtuzumab or natalizumab in the UK.
I then went on to say that if I saw her I would examine and investigate her to make sure she didn't have highly active disease, which could make her eligible for other treatments apart from platform therapies. This is the problem when I get sent information that is incomplete.
In some countries such Australia, these sorts of discussions are not relevant as all the DMTs are licensed for active MS and all DMTs are available to used as the neurologist and the patient see appropriate.
Thank you, Gavin. I appreciate the nuances between a newsletter post and an actual patient of your own. Nonetheless, you know well that very many of your colleagues would just lob the responsibility back to the patient with scant regard to the internal discombobulation that is occurring.
Sure. With what I have heard - caveat as before re 'is this actually a thing?' - about the jab, then if you can't get a fag paper between them it'd be ofatumumab from a convenience point alone.
To broaden it, the idea now - 28y in - of potential fire and forget therapies that may have some IRT element would skew my choice.
So patients can assimilate the issues then and make a choice. I agree for convenience ofatumumab will win hands down. If you weren't switching from ocrelizumab to alemtuzumab would you have asked to switch to ofatumumab?
I thought a lot about this and that felt a very sideways move. Much talk of long-term anti CD20 and is it a good thing, the vaccine thing (which doesn't scare me but really pisses me off) with Of is still up in the air and I struggle to see how it will land so differently from Oc.
I'd have HSCT tomorrow. That is looking less and less likely with the pandemic, my age, likely pretty crap level of SC that I would generate to be harvested and reinfused, lack of access to private funds, a strong desire not to go to a more 'relaxed' country to get it, etc.
Alem not only gives me a way to eventually enjoy vaccine protection similar to the next person, an IRT that is the chemical version stem-cells ,though I think the reconstitutive benefits are long behind me so not expecting any and a degree of closure to endless drug-taking.
Morning.
I find the idea of ultimately passing the decision to her with the message of 'you choose' extremely problematic. I realise that when you are writing it all down it may not always convey nuances, so I comment with that in mind.
When you are diagnosed you are, to put it bluntly, in a complete shitstorm of emotion. New demands, fear, uncertainty doubt, general 'what-ifs' and it is appalling. Then to have the person who you'd like to be your rock regarding the medical stuff turn and tell you that the choice is all yours is something that, in the malestrom, you probably just accept.
Whatever the doctor thinks and however hard they work to minimise it, there is and always will be a power imbalance between patient and doctor. I recently discussed this at some length with a cardiologist friend, who is extremely experienced, but just caught a cancer diagnosis of their own. They were reflecting on what it was like to sit in front of the expert and just feel 'junior and scared' again. If it can happen to them then imagine a non-medic?
Trial aside: I would suggest that they want some sort of steer, even if you couch it in the six and two threes wrapper. They want to trust you.
After all, deep down, were you to have to make the choice for you or your close relative in her shoes then you'd know which way you'd go.
I am a grumpy old sod who has different views. I am trying to remark from the POV of three people I have spoken to recently. Their view is so very different. The main emotion is fear. It permeates everything else. Can you imagine the irrational fear that 'what if I chose the wrong one?' as well. As illogical as you may know that to be, for them it it is just another layer.
Best,
Dominic
PS: Nothing said about Covid vaccines etc going forward. I thought I heard murmurings about ofatumumab not having such a deleterious effect as ocrelizumab but feel on v shaky ground regarding this. Care to comment? Thank you
Very good point. One option I always add is for the patient to choose the option of you making the choice for them; i.e. paternalistic medicine.
To be honest I don't have enough information about this particular patient to say x or y. If I was seeing this patient myself, which I could do if I had a private practice, I would want to know a lot more about her life, job, plans for a family, etc.
I also need to know about her MS. She may be better off starting on DMF or oral cladribine rather than an anti-CD20. If her scan and CSF analysis shows she has very bad MS I would be guiding her towards alemtuzumab.
To be honest when it comes to head-2-head efficacy comparison in relation to an anti-inflammatory decision between ocrelizumab and ofatumumab the differences are not meaningful. I would give ocrelizumab the theoretical edge in terms of smouldering MS and I ofatumumab the edge on safety (it seems to be less immunosuppressive).
The vaccine data on ofatumumab is not available yet. Let's wait for that before making any claim that it is better than ocrelizumab.
Let’s say that this lady travelled a lot and may find a 6-monthly infusion difficult then self-administered ofatumumab would be the agent of choice. On the other hand if she was needle phobic in relation to injecting herself then ocrelizumab would be the recommendation. If she was diabetic it would be ofatumumab to avoid the need for steroids to prevent infusion reactions.
The point that needs to be made is that when deciding on a DMT for a patient it is the subtle things that make you decide on which DMT to recommend. Yes, I am sitting on the fence because I have to ;-)
I was very happy to finally see this comment:
“I also need to know about her MS. She may be better off starting on DMF or oral cladribine rather than an anti-CD20. If her scan and CSF analysis shows she has very bad MS I would be guiding her towards alemtuzumab.“
She is young and newly out of college. Her best option for convenience, future fertility planning and holding to “time is brain” would be IRT.
The trial gives her a shot at a possible IRT. This is well founded but she may get the comparator arm (or the trial may fail- although this seems unlikely).
Why not go with a definitive IRT? As a provider I would at least discuss these therapies with her- add them as options. Ultimately doctor and patient need to understand potential risks (doctor informs patient) and the motivation of the patient (is she conservative or aggressive in her approach to treatment).
I am thankful to hear your recommendation for the severest MS outlook is Alemtuzumab over oral Cladribine. This was the most insightful nugget of the entire case history for me.
Thank you for these long formats and detailed follow-ups.
Definitely worth the subscription!!
If I had MS I would want alemtuzumab or HSCT. Hope that puts my bias into perspective.
Thanks. Hopefully, your subscription will be used for something good.
Return on my investment exceeds expectations 😉
Prof.....how can you steer this patient towards alemtuzumab based on CFS and MRI analysis? it is a second line agent. I'm asking for my own interest of course and slight frustration that some neurologists are not willing to apply the 'guidance' to suit patient choice
The guidelines are just that a guide. If the patient had an enhancing lesion, poor MRI and very high NFL levels and you were worried about her long-term prognosis you could potentially offer her alemtuzumab under exceptional circumstances. Medicine and neurology is not an algorithm, but an art and therefore you need to be flexible.
Thanks Prof. Sadly, not all neurologists think alike and will act like their hands are tied. Despite my own poor prognosis, i still received the NHS leaflet with the injectables 'circled' as my options. A lot of patients will not investigate any further and will miss out on potentially better outcomes as a result. Too many poor artists it seems
For US-based readers, insurance is a consideration. Typically, ocrelizumab goes through medical insurance because it is an infusion; ofatumumab goes through prescription insurance. I have found that my medical insurance is typically easier to deal with vs. prescription insurance - so not worrying about interruption in my medication delivery is a pro for Ocrevus. This may not be the same for others, but it is worth considering - albeit likely overwhelming, since most US patients don't know the difference between these two types of insurance...I have a Masters in Healthcare and still find it difficult to navigate.
Hi Dr. G., if you had a patient that had been on ocrelizumab for 5 years and paused for a year to improve vaccine response, would you have any preference when they restarted treatment between Ocrelizumab vs Ofatumumab? (Happy for quick thoughts or to submit as a case study if you prefer.)
Depends on whether or not you think ofatumumab is a low-dose anti-CD20 therapy and if you need CNS and deep tissue penetration or not. I suspect more ocrelizumab gets into the CNS than ofatumumab.
I'm back! Facing the same decision about whether to restart Ocrevus or switch to Kesimpta after a 10-month pause to hopefully get some antibodies from the bivalent Covid vaccine ahead of the holidays. (I am feeling very lucky that I repopulated into the normal levels of CD20 cells in just 10 months after 6+ years on the drug.)
Any new thinking on this topic? Given that I seem to repopulate B-cells quickly and Ocrevus is easier with my specific insurance plan, I'm inclined to stay on Ocrevus. I doubt that there will be another interesting vaccine for a while, so likely won't need to pause again.
[Side note - I hate Covid. I hate having to do daily math about my risk level based on scraps of data from cities far from where I live. I hate having to make big decisions about my MS treatments with major blind spots. I hate that most of my friends/family/co-workers have no qualms about being asymptomatic spreaders of a virus that made me sick for months over the summer. I hate that those same friends/family/co-workers also have no qualms about freely spreading their flu/RSV/bronchitis/other germs this season. I hate that rapid tests have turned out to not be a very good tool for me to have in-person interactions with other people. And I hate that it will be another 5ish months before the weather is good enough for outdoor socialization again.
If anyone has found a magical place with outdoor-friendly weather most of the year, that is serious about minimizing community levels of Covid and that lets people with MS emmigrate, please share!]
There is little to choose between ocrelizumab and ofatumamab in terms of peripheral B-cell depletion and anti-inflammatory effects. I think you get more CNS penetration with ocrelizumab and hence a possibly greater impact on CNS-resident B-cells and possibly end-organ damage.
OK, sounds good. Given that and the other factors important to me, it sounds like another year of Ocrevus is best plus some blood tests closer to the 6-month mark after doses to see how quickly I'm actually repopulating B-cells.
Hmm, I'm not sure how to weigh CNS/deep tissue penetration. Positive for OCB 14 years ago, so CNS involvement in the past (hasn't been tested since). CD19 back to 14% / 315 mm3 with 11 pause in Ocrelizumab. Seems like erring towards the potentially stronger option would make sense. As an added bonus, 2x/year infusions are easier to deal with insurance-wise than monthly shots (this bonus is specific to a particular US insurance plan, not all US insurance plans).
Thanks!
I hope you realise why it is so important for this patient to be enrolled in the high-dose ocrelizumab study. It is testing a hypothesis that I put forward 20+ years ago when I was doing my PhD that CNS resident B-cells and plasma cells are important drivers of progressive or smouldering MS pathology.
If high-dose ocrelizumab is confirmed to be more effective than standard-dose ocrelizumab then there is little doubt about what the choice of anti-CD20 will be in this patient and it will increase the race for CNS penetrant DMTs that target intrathecal B and plasma cells.
I would give the high-dose studies an over the odds (>50%) chance of being positive; my optimism is based on biology and is why we are doing the SIZOMUS trial.
One of the distinct advantages of any MS treatment is the ability to reduce the need for hospital attendences. If you live in a rural/remote area then the opportunity to give injections in the home is a huge advantage; it saves on travel costs, time and also accessibility to hospitals during poor weather. It frees up staff to provide satellite clinics in more rural areas which is a much better use of resources.
Dear sir, your newsletters provide us patients great insights into the disease and its treatment. You said you would want her to be on oral cladribine or alemtuzumab rather, if her MRI reveals enhancing lesions and CSF examination reveals raised nfl levels, and end organ damage/ brain volume loss should not be considered here as we are not comparing anti CD to other high efficacy treatments.
Could you please explain what therapies you refer to when you say high efficacy treatments.
Does oral cladribine also fall into that category of high efficacy DMDs and do you consider it to be better than anti CD20 therapies in terms of preserving brain and spine volume?
Thanks and regards.
Apologies, for the confusion. With the information, she gave me I interpreted her case as being active MS and not highly active or rapidly evolving severe MS. Based on this she would be eligible for cladribine, alemtuzumab or natalizumab in the UK.
I then went on to say that if I saw her I would examine and investigate her to make sure she didn't have highly active disease, which could make her eligible for other treatments apart from platform therapies. This is the problem when I get sent information that is incomplete.
In some countries such Australia, these sorts of discussions are not relevant as all the DMTs are licensed for active MS and all DMTs are available to used as the neurologist and the patient see appropriate.
Thank you, Gavin. I appreciate the nuances between a newsletter post and an actual patient of your own. Nonetheless, you know well that very many of your colleagues would just lob the responsibility back to the patient with scant regard to the internal discombobulation that is occurring.
Can I lob it back to you then? What product would you choose; ocrelizumab or ofatumumab?
Sure. With what I have heard - caveat as before re 'is this actually a thing?' - about the jab, then if you can't get a fag paper between them it'd be ofatumumab from a convenience point alone.
To broaden it, the idea now - 28y in - of potential fire and forget therapies that may have some IRT element would skew my choice.
In a pure Oc vs Pf world, definitely the Of.
So patients can assimilate the issues then and make a choice. I agree for convenience ofatumumab will win hands down. If you weren't switching from ocrelizumab to alemtuzumab would you have asked to switch to ofatumumab?
I thought a lot about this and that felt a very sideways move. Much talk of long-term anti CD20 and is it a good thing, the vaccine thing (which doesn't scare me but really pisses me off) with Of is still up in the air and I struggle to see how it will land so differently from Oc.
I'd have HSCT tomorrow. That is looking less and less likely with the pandemic, my age, likely pretty crap level of SC that I would generate to be harvested and reinfused, lack of access to private funds, a strong desire not to go to a more 'relaxed' country to get it, etc.
Alem not only gives me a way to eventually enjoy vaccine protection similar to the next person, an IRT that is the chemical version stem-cells ,though I think the reconstitutive benefits are long behind me so not expecting any and a degree of closure to endless drug-taking.
Dom - why would you generate a low level of SC to be reinfused? is this age related or affected by previous treatments please?
I gather that the volume and/or quality declines with age.