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We talk a lot about CNS resident B cells driving MS and using anti CD20 therapies to deplete them.
Do these B cells ever mature into non anti CD20 expressing plasmablasts? If they do mature into plasmablasts, what sort of strategies would work to regulate them?
CD20 are going to perform badly at this as they won’t get in the CNS. The action is in the periphery like the blood and lymph glands
Good question. I am assuming they do mature into non cD20 expressing plasmablasts and there is evidence to support this by looking at their B cell receptors which you can sometimes find in the blood and the spinal fluid.
You stop the cells entering CNS so they are not there to convert into plasmablast
MD – what about the cells that are already in there? how does alem and HSCT differ from anti CD20 in targeting these cells? its widely accepted that treat early is best approach but surely some cells have already entered the CNS no matter how early?
Alem doesnt get the cells in their either and hSCT wont get most of them.
Yes some cells will be in early and people may continue to deteriorate and I think we need to target stuff inside the brain as well as the peripheral blood
Take them out with cladribine first and then anti-CD20?
Hi MD, which Covid antiviral would you recommend for MS patients (some sort of ranking of preference)? Paxlovid followed by Molnupiravir? Are there any others (of course we should probably take whatever is available but this is assuming all options are a possibility). Thank you as always 🙂
Based on efficacy paxlovid (~90% reduced risk of hospitalisation) is more effective than monupiravir (30% reduced risk of hospitalisation…the studies were not the same) if you are hospitalised you may get remdesivir. Antibodies may be given
This looks interesting. Review in Nature about a recent paper:
Epstein–Barr virus sparks brain autoimmunity in multiple sclerosis
Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM
we have reported on both of these papers
In a recent Swiss twin study it was found that increased production of CD25 cells was the most noticeable alteration in immune blood cells people with MS as opposed to their unaffected identical twin in what the researchers believe may be the “big bang” of MS. If this turns out to be the case, how might that change the way pwms are treated initially? Or would it even change anything?
Incredible b cell biology
Marginal zone B cells acquire dendritic cell functions by trogocytosis
Trogocytosis (Greek: trogo; gnaw)
Bone marrow transplant: What is the impact of chemotherapy on the brain?
In their work, the scientists show that after busulfan chemotherapy, microglial cells completely lose this regenerative capacity, and that many of these cells die by senescence.
However, this process would not be harmful to the brain, since after transplantation, the disappeared cells are quickly replaced by bone marrow-derived cells (macrophages). The microglial cells eliminated by busulfan chemotherapy leave empty niches in the brain that are soon filled by bone marrow-derived macrophages. These macrophages then adopt the morphology and behavior of normal microglia. Future studies will aim to determine whether these macrophages adopt all the properties of endogenous microglial cells in the brain.
I’ve been on Natalizumab since 2010 but likely switching to Cladribine due to becoming JC virus+ in 2020.
I have been getting many mixed messages from my neurologist in the last few months. Last year he told me that, due to being JC+, Cladribine was NOT an option for even with a lumbar puncture prior to starting as “there was always a chance PML was lingering in the background”. He told me if I got PML and I had begun Cladribine “you wouldn’t survive it”. He was absolutely clear that even with an lumbar puncture he would not entertain it.
He then changed in December to tell me we COULD go ahead with Cladrbine and we DIDN’T need a lumbar puncture… His message (via my MS nurse) was that it wasn’t necessary as “it only made a slight difference”.
Now, as of last week, he is saying that I can have Cladribine but would strongly advise a lumbar puncture.
I really don’t want a lumbar puncture, but if it’s absolutely necessary, I will reconsider. I just want to know which stance of his I should follow – the line that it is crucially important or the “doesn’t make much difference” stance. If it doesn’t make much difference, I don’t want to put myself through it. I’m struggling with the mixed messages and to know which to side with.
So, in summary, before beginning Cladribine does a lumbar puncture make much difference? In particular, for those in my case, switching from Natalizumab / those who are JC+ at the time of switching.
Thanks in advance.
Thanks Stuart, this issue has been a little contentious, which has to do with (i) sensitivity of testing and (ii) understanding the impact of cladribine on cells of adaptive immunity. Firstly, CSF JCV testing is not very sensitive; even if you have PML, the result can be negative, particularly in cases where nothing can be seen on MRI either. It is therefore paramount that an MRI head is being obtained and reviewed by a radiologist with experience ruling out PML, but CSF is not mandatory. This is, of course, on the basis there are no symptoms suggestive of PML, in which case an LP should always be done. Secondly, there has been *no* reported case of PML with oral cladribine. Why? Because the cells that are important to tackle JCV are CD8+ T cells. However, this cell type is only mildly suppressed by cladribine such that – unlike natalizumab, and in some cases fingolimod and dimethyl-fumarate – protection against this opportunistic infection remains likely preserved. Indeed, my hypothesis is that the unique dynamics of cell depletion & recovery with cladribine could be conducive in situations like yours since disease control appears to be combined with a negligible effect on protection from PML. Don’t take it as medical advice, please; it’s my evidence-based opinion !
Thanks ever so much for your thoughts, Klaus. Very much appreciated.
What about this re cladribine and PML? Not MS I know and other confounding factors but still makes sobering reading re PML and cladribine…..
Case Reports J Clin Virol
. 2017 Mar;88:17-20. doi: 10.1016/j.jcv.2016.12.005. Epub 2016 Dec 14.
Progressive multifocal leukoencephalopathy in a patient with systemic mastocytosis treated with cladribine
I’ve shared the paper with you. If you inspect figure 1, you will see that from 2012 onwards, i.e. 4 years before PML, the patient had had lymphocyte counts of <0.8, i.e. below the minimum level that would be required as per smpc for (re-) treatment with cladribine tablets. This patient, however, had five further courses of treatment, despite total lymphocyte counts as low as 0.1. Not a situation you will encounter in pwMS, unless there is significant comorbidity (or medical negligence).
What about pwMS who have recovered from PML would you still be as confident about cladribine?
Interesting, thanks. What about pwMS who have recovered from prev PML – would you still be confident with cladribine?
It will depend on the situation. If Natalizumab was key in the development of PML, adaptive immunity is essentially intact and with the semi-selective depletion cladribine induces I’d expect the risk would be small. Different ball game if systemic T cell depletion were involved; I’d be more circumspect then.
Hi Prof K (maybe MD you might know?) but there are quite a lot of people reporting worsening of walking (especially balance) after Ocrevus ( https://www.drugs.com/comments/ocrelizumab/for-multiple-sclerosis.html#:~:text=Ocrelizumab%20has%20an%20average%20rating,50%25%20reported% ) What would cause this type of worsening? Does this automatically mean you are SPMS? Does it mean the drug isn’t working for you? Could the portion of B cells that are killed affect MS? Of course you can say “MS might’ve been worse had nothing been done” but I am almost certain this is not the case with a lot of people commenting.
(a) The question is what is the reason for taking ocrelizumab is it to block relapses or slow progression….if it is the latter the question is the worsening due to active MS or not, because if the worsening is not due to active MS then it may not respond well. If there is worsening? Would there be more worsening if you weren’t taking anything?
(b) If there is worsening due to ocrelizumab what is the cause….
To avoid issues I will look at CD20-responsive non MS conditions and there are reports of acute worsening (PMID: 25115501 DOI: 10.1016/j.jns.2014.07.055;PMID: 29433095 DOI: 10.1016/j.msard.2018.02.004), why would this occur I dont know but can speculat that it ocrelizumab is removing regulatory cells
Thank you MD and apologies for a delayed response – Russia/Ukraine news got the better of me. (a) I’m trying to understand this point a little better… what do you mean by it “not responding well” if someone takes Ocrevus to slow progression and worsening is not due to active MS? Alternatively, if WAS due to active MS, would that mean Ocrevus isn’t working just yet and one would need to give it more time or just that this medicine is incompatible with the user? Regarding the second point (b) if Ocrevus removing regulatory cells would be the reason behind worsening – does that mean you would expect this to happen after every infusion? Do you think things might get worse the longer you are taking Ocrevus infusions? Could worsening be more likely to happen the longer your MS has been left untreated (i.e. more damage)? And lastly… if one wanted to switch to Alemtuzumab as an IRT – would you expect similar worsening? Apologies for the barrage of questions, although the way this seems to be effecting people is incredibly intriguing…and scary!!
in europe ocrelizumab is approved for active (MS lesions) MS but in US it is approved for all MS, Therefore the Euopeans were not convinced it was a active in non active MS
If ocrelizumab is targetting regulatory cells it is hard to know what would happen on each occasion
Thank you for your thoughts and analysis MD – Happy Sunday, hope you get some rest time!!
Have any of you heard any news or talk lately about ibudilast for multiple sclerosis? I read somewhere that it is known to act on microglial activation, which is interesting as to any possible effects on CNS immune cells.
plan for another study I think
What cause ms ,what makes it worse?
Memory b cells infected with ebv ?
Cerebral venous flow ?
T cell ?macrophages?
Anything i dont remmenber at the moment?
Its the lungs and their microbiome (didnt know lungs had a microbiome)
The lung’s microbial flora regulates the brain’s immune reactivity
🙂 I’ve seen it too
Question Are T-cell responses to the SARS-CoV-2 Omicron variant conserved in anti-CD20–treated patients with multiple sclerosis after COVID-19 messenger RNA vaccination?
Findings In this cohort study of 20 patients treated with ocrelizumab, Omicron spike-specific CD4 and CD8 T cells were detectable in approximately half of patients 6 months after the second vaccine dose, and cytotoxic T-cell responses increased following the third dose. Frequencies of T cells specific to the Delta and Omicron variants were lower compared with the vaccine strain, both before and after receiving a booster dose.
Meaning In this study of anti-CD20–treated patients with multiple sclerosis, the vaccine-induced T-cell responses were little affected by the mutations carried by Omicron and might prevent severe COVID-19 infection, and a third vaccine dose improved cytotoxic T-cell responses against Omicron.
Responses After a Third Dose of mRNA COVID-19 Vaccine Among Patients With Multiple Sclerosis Treated With Ocrelizumab
Circulating Memory B Cells in Early Multiple Sclerosis Exhibit Increased IgA+ Cells, Globally Decreased BAFF-R Expression and an EBV-Related IgM+ Cell Signature
Thanks learned about Belimumab trial (NCT04767698). This is a human monoclonal antibody that inhibits B-cell activating factor same target as tablumab..em!
Together, these data suggest that the B cell compartment is dysregulated in MS regarding aberrant MBC homeostasis, driven by reduced BAFF-R expression and EBV reactivation
D you think Ebv its behind all this?
Or its a mix between virus an tge immunne system?
hopefully someone will do a journal club on this one
Primary Outcome Measures:
1. Pneumococcal vaccine antibody response
[ Time Frame: Month 25 ]
Is this a good trial design?
Well i stop taking milk a while back and start taking iogurt last week
And did not feel all that great ….lolllllll
Milk may exacerbate MS symptoms