39 Comments
Jul 26, 2023Liked by Gavin Giovannoni

My lumber puncture was negative for OCB but I continue to progress (seems to be speeding up in recent years) so what would this mean for me? Thanks!

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author

Most people who are OCB-ve at diagnosis convert to being OCB+ve later on. As with all tests there is a false negative result and when re-running the sample the result is positive. I think that when we have definite proof of the cause of MS OCB-ve MS will be another disease.

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Jul 26, 2023Liked by Gavin Giovannoni

Thank you for your response but my LP was more than 10 years after diagnosis when i had already transitioned to SPMS but maybe another one would provide a different result. Not sure I'll be volunteering myself for another one anytime soon though :-) Does your answer suggest I have something different to the 'normal' MS then?

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author

Yes, in general OCB-ve MS has a better prognosis and behaves differently to OCB+ve MS.

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Jul 27, 2023Liked by Gavin Giovannoni

whether you have something different to the 'normal' MS? well, I understand the question. I've been dx last year, 45 yo, with RRMS, EDSS 3,5-4, but symptoms may have appeared 10 years earlier. OCB negative, NFL normal, still deteriorating (subjectively, at a fast pace). my neuro admits is could be the progessive form, but until further evolutions she prefers to stick with the RRMS (there are also some administrative issues, being unclear whether she could give me ofatumumab further if PMS became the dx). still unclear whether kesimpta is effective in my case. managing ms-uncertainties is a full time job. haha.

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author

In the ocrelizumab PPMS trial we excluded patient who didn't have a positive CSF analysis (OCBs or raised IgG-index). We really don't know if anti-CD20 therapy works in OCB-ve MS.

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my neuro is particularly concerned with active lesions on my 2nd MRI, after 9 mo of Tecfidera. so, she proposed an anti-b20, for at least 6 months, and, as an option of last resort, alemtuzumab. In Romania I have to fail two dmt-s before being eligible for lemtrada. ahsct exists only anecdotally-I heard of 3 cases who performed the procedure in Moscow/Praga, but only one seems kind of beneficial; all 3 have about my age. haha. the famous therapeutical window - sounds brutal, but entirely possible.

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Jul 26, 2023Liked by Gavin Giovannoni

I couldn't take part in the cladribine because my lumber puncture showed my MS isn't active. Does that mean I wouldn't qualify for this trial?

Mad, that nobody has looked at this drug since that early trial.

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author

Yes, you could still be eligible for the SIZOMUS trial provided your CSF has OCBs.

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Jul 26, 2023Liked by Gavin Giovannoni

I'm a little lost. You say "The implication is that if we can scrub the brain clean of B-cells and plasma cells and reduce CNS Ig production, we may slow down or stop smouldering MS. " However, in other posts you have said that, in your opinion, EBV plays a central role. Why not focus on anti EBV strategies and leave the B cells alone? I know EBV homes in on B cells, so there is a close association but eliminating B cells doesn't necessarily mean EBV is eliminated. Is MS a cause or a symptom? Why can't it be smouldering EBV as the real culprit?

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Yes, but B-cells is where EBV resides and the B-cell population with the CNS may be the reservoir for EBV. We also don't know how EBV causes MS and if it is doing this via autoimmunity once the latter is triggered we may have to target adaptive immunity downstream of EBV. The latter is the so-called hit-and-run n hypothesis.

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Then you have two variables 1) EBV and 2) B cells. Do you know, for certain, how a B cell causes MS or is the evidence just anecdotal that depleting B cells limits progression and why remains unknown? Aren't both variables each as valid as the other?

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Hello Mr. Scott- They are what they are. Here is my non-medical “MS101” reply, albeit not asked for, so you have to validate it for yourself: EBV is a variable existing in something like 95% of the population, and yes, it appears that the infection is needed in order to later develop MS. But you have to have additional factors for MS to develope (genetics, Vit D & sunlight; comorbidities, etc…). Only 1 of 333 people (95% with EBV) develop MS in the general population; do the math. And MS is still multi-factorial and the going wisdom is that once the process has begun, removal of EBV may not have much of an impact.

B cells produce antibodies which munch at your CNS, mistaking it for an infection of some sort (the so called “misguided attack”). What makes them do this is uncertain, but it is known that fewer of the right type of B cells you have , then the less misguided attack you have, because the antibody “soldiers” are no longer on the CNS battlefield, they have been depleted. Hence, another actual infection does not bode well with no antibodies to fight it, and you sometimes need supplemental care. It’s a risk-benefit call where especially if you are younger, going for depleted B calls may be an advantage in terms of MS damage versus an infection.

Perhaps my layman’s explanation might be helpful? Or probably not. You may see it differently. Good luck to you.

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founding

This sounds promising and exciting for NEID pwMS. I’m in the camp of Joe’s thinking that my testing was done many years ago, and in addition, at my age, I wouldn’t be a candidate for a drug trial. However, what is puzzling to me about cyclosporine etc is, like chemotherapies, that there will always be a risk/benefit analysis. As you’ve said, it should be treated like cancer or stroke. Anything that will stop progression without all of these various MS labels.🌷

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Jul 26, 2023Liked by Gavin Giovannoni

I was accepted onto the Sizomus trial but was unable to continue as my lumbar puncture was negative despite being positive at diagnosis. Wafa contacted my hospital who confirmed it was positive previously. Is it possible for the bands to disappear? I thought not I would be very interested in your opinion thank you.

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author

Yes, OCBs do disappear in patients on certain treatments. Early data suggest that 50% of cladribine treated patients lose OCBs. About 30% of AHSCT patients lose OCBs within about 3-5 years. The data on natalizumab is inconsistent, but suggests about 20% of patients lose OCBs over time. We did a study on alemtuzumab treated patients and at 3-years they had not lost OCBs. However, three years may be too short a period of time to look at OCB loss as long-lived plasma cells live much longer than than that and possibly decades.

In the SIZOMUS trial we are looking at 2 years; but ixazomib is meant to kill plasma cells.

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Thanks for your reply. I've been on Gilenya for 13 years and Avonex before that not the ones you mention above. Maybe Gilenya can be added to the list. Good luck with the Sizomus trial!

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Jul 26, 2023Liked by Gavin Giovannoni

I would also be interested in knowing if bands disappear. Thanks for asking that question.

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Jul 26, 2023Liked by Gavin Giovannoni

What about BTK in combination (or shortly after) Lemtrada / Mavenclad as a way to clear the pathway so to speak

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author

Yes, it makes sense to use BTKi as maintenance therapies after depletion. I am sure the pharma companies developing BTKi will be planning these studies.

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Jul 27, 2023Liked by Gavin Giovannoni

Thanks. I will have a look who is doing it and contact them.

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Jul 27, 2023Liked by Gavin Giovannoni

“the brain and spinal cord clean of B-cells and plasma cells”

3 questions:

Do people without MS (or other brain diseases) have B cells and plasma cells in the CNS ie is this a normal state of affairs?

Why do B cells and plasma cells (in people with MS) end up in the CNS and stay there (in the case of plasma cells for a long time)?

If therapies can scrub the CNS clean of B cells and plasma cells, what stops them coming straight back?

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Q1: Do people without MS (or other brain diseases) have B cells and plasma cells in the CNS ie is this a normal state of affairs?

Yes, memory B-cell traffic through the CNS in normal people. Plasma cells only set-up shop in the CNS if there has been an antigen-specific signal to stimulate their formation, e.g. after an infection or when an autoimmune disease occurs.

Q2: Why do B cells and plasma cells (in people with MS) end up in the CNS and stay there (in the case of plasma cells for a long time)?

A very good question. We think this happens because the stimulus or signal that is driving T-cell and B-cell activation persists and hence leads to the formation of plasma cells. Plasma cells are of two main types; short-lived and long-lived. The long-lived create a niche and live for decades and some immunologists say for life. This is why people in their 60s, 70s and 80s still have detectable antibodies to childhood infections and vaccines.

Q3: If therapies can scrub the CNS clean of B cells and plasma cells, what stops them coming straight back?

if you treat the cause of MS and remove the stimulus the B-cells and plasma cells should not return. If you don't treat the underlying cause these cells will come back. The next question is what is the cause of MS? If it is EBV we need therapies to prevent EBV infection, i.e. antiviral. If the cause of MS is autoimmunity we need immunosuppression.

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Jul 27, 2023Liked by Gavin Giovannoni

What would hapen if b cell and plasma cell were removed from CNS to JC virus?

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Not much. What controls JCV is T-cells. As long as you maintain CNS trafficking of T-cells the immune system should keep JCV in check.

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founding
Jul 27, 2023Liked by Gavin Giovannoni

Hi Prof G. I’d be interested in your study of anti-CD19 targeted CAR T-cells. I was also wondering - you say BTK inhibitors are ‘close to market’ - how close? Can one go on more than 1 round of Cladribine if the 2nd round is Cladriplas? Thank you

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We are expecting the Evobrutinib phase 3 results in the third quarter of this year. If positive then there is the regulatory submission and assessments which take about 12 months. After that the market access delays. So if all goes to plan there may be a BTKi on the market by late 2024 or early 2025.

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Jul 26, 2023Liked by Gavin Giovannoni

You could use temozolomid( it crosses the BBB), has low side effects on glioma patients and it depletes also peripheral lymphocytes, not only central. I think temozolomid could treat MS better than aHSCT.

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author

Yes, temozolomide is immunosuppressive and could potentially work in MS. However, its safety profile may make it difficult for it to gain wide use compared to other DMTs. For example, anti-CD20 therapies are very effective and have a very good safety profile in the short to intermediate term.

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Jul 26, 2023Liked by Gavin Giovannoni

Sorry I don't know of anywhere more germane to post this question but I would be fascinated to know what you made of the recent paper on the correlation of MS with periodontitis.

https://pubmed.ncbi.nlm.nih.gov/37478676/

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This is not new data. The association between periodontitis and MS has been known for sometime and is on my list of things to screen for and treat in the holistic management of MS. It is a chronic infection that may speed up MS worsening by stimulating innate immunity peripherally.

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Jul 26, 2023Liked by Gavin Giovannoni

Was there a “not” left out of this sentence?

“The transplant physicians eventually derisked the renal toxicity associated with cyclosporine, which is why I am surprised it was taken forward in MS.”

My understanding was that cyclosporine was a promising treatment, but the renal toxicity was an impediment to its use. What am I missing?

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Yes, "not" now added. Thanks.

Since the original trial was done a new lipid-nanoparticle formulation of cyclosporin was developed that allows better control of blood levels and as a result has reduced the incidence of nephrotoxicity. However, nephrotoxicity is still a problem.

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At Minho university in Portugal, Dr João Cerqueira is conducting several studies, one of them is high dose rituximab (or ocrelizumab, I'm not 100% sure) to wash microglia and stop smoldering MS.

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author

Rituximab has been looked at and it doesn't clear the CSF of OCBs. In collaboration with a Russian group we showed that intrathecal rituximab actually increased CSF kappa FLC levels rather than decreasing them. I think the case of high-dose ocrelizumab is much stronger. Ocrelizumab is also more potent that rituximab.

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Jul 26, 2023Liked by Gavin Giovannoni

Why csf kappa flc increasee?

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It's definitely ocrelizumab, the same doctor present In the last AAN a long term study with ocrelizumab

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An important post-hoc analysis of the phase 3 ocrelizumab trials, which used a fixed dose of 600mg intravenously every six months (Hauser et al. 2017; Montalban et al. 2017), suggests we may need higher doses of anti-CD20 therapies. Smaller trial subjects got given a larger dose of ocrelizumab than larger subjects. For example, someone weighing 60 kg was given 10mg/kg of ocrelizumab 6-monthly compared to 5mg/kg for a trial subject weighing 120 kg. When subjects were divided into four groups or quartiles representing four dosing levels based on measuring peripheral blood drug concentrations (Hauser et al. 2023), no differences were found in relation to the treatment effects of ocrelizumab on relapses and MRI activity. However, subjects who received higher doses and had more significant B-cell depletion were less likely to have worsening disability (Hauser et al. 2023). This higher-dose treatment effect on disability worsening was seen in both the relapsing and primary progressive populations (Hauser et al. 2023).

Therefore, people with MS may require higher, and not lower, doses of anti-CD20 therapy, which may be having an effect due to better CNS penetration. As a result of these post-hoc analyses, two high-dose ocrelizumab trials targeting relapsing and primary progressive MS are currently being performed (NCT04544436, NCT04548999).

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Very interesting. My CSF was positive for oligo clonal bands on diagnosis 2 years ago. If I lived closer, would definitely participate in the trial.

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