15 Comments
Oct 13, 2021Liked by Gavin Giovannoni

Is brain volume loss vital to counter right from diagnosis or does it become more important once initial high inflammation is controlled?

Also, do you perceive a time when AHSCT would be offered before treatment failure of prognostic markers are poor? (Or do you feel it should be?).

My best wishes to this gentleman and I so hope he gets some answers and benefits from therapy soon.

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Re: "do you perceive a time when AHSCT would be offered before treatment failure of prognostic markers are poor"

Yes, this is why I am lobbying or nudging the MS community to be able to offer AHSCT first-line in pwMS with a poor prognostic profile.

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Re: "Is brain volume loss vital to counter right from diagnosis"

From diagnosis; once you have lost brain volume it is irreversible. DMTs, particularly highly-effective DMTs, should be considered preventive therapies, i.e. to prevent end-organ damage.

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So if antiCd20s do this so badly why are they being started with such increasing frequency? Is this setting up a whole cohort of newer PwMS to still have significant issues 20 years later despite good initial reduction in relapse rates which seems to be driving use of these meds?

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Because the MS community are fixated with relapses and focal MRI activity and not end-organ damage. This is why we need to go beyond NEIDA or NEDA-2 and tackle smouldering MS.

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founding

And because, pre covid, it was convenient for doctors and patients. Presumably still largely true for doctors, less so for patients.

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What measures or markers should pwms be looking for in their MRI reports regarding brain volume. I know my reports done by a 3t MRI typically state no significant brain volume loss. Are these accurate or do we not have good measures at this point to track this?

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Re: " no significant brain volume loss"

This refers to macroscopic brain volume loss, i.e. that what is visible with the naked eye. Very few centres use accurately measured brain volumes measured with specialist software.

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It may also relate to dose. It seems that high-dose anti-CD20 therapy is better than low-dose anti-CD20, which is why we are testing 600mg vs. 1200mg vs 1800mg of ocrelizumab to see if the higher doses are better at targeting smouldering MS.

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Oct 20, 2021Liked by Gavin Giovannoni

Interesting point on brain volume loss associated with Rituximab. I was wondering why there was so little data available on PBVL for the novel CD20 depleters. Or at least it eludes me.

May I ask where we can submit our case for a potential evaluation in these case scenarios?

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The data is available and the reason why there is not much noise about it is that it is not that good.

In short ocrelizumab and ofatumumab reduce BVL to about 0.30 - 0.35% per annum. Ocrelizumab was superior to interferon beta-1a (Rebif). Ofatumumab was not superior to teriflunomide. Fredrik Piehl told me that in a study in Sweden rituximab-treated patients had more brain volume loss than interferon-treated patients.

The MS community seem to ignore uncomfortable truths and one of them is the observation that anti-CD20 therapies, despite being very good at switching of focal inflammation (relapses and MRI activity) are not that effective at protecting the end-organ (BVL). Why?

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Oct 17, 2021Liked by Gavin Giovannoni

Hi Gavin, thanks for another really informative/interesting post. I just wondered what data are you referring to re rates of anti-Rituximab antibodies being 5-8%? I’d like to read it. Thanks!

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5-8% actually refers to NABs. The incidence of ADAs (binding and neutralizing) are actually much higher.

Dunn et al. Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies. Mult Scler. 2018 Aug;24(9):1224-1233.

Background: Rituximab is a chimeric monoclonal anti-CD20 B-cell-depleting antibody increasingly used off-label in multiple sclerosis (MS). The clinical relevance of anti-drug antibodies (ADAs) against rituximab in MS is unknown.

Objective: To determine frequency of ADA in relation to B-cell counts, allergic reactions and clinical efficacy in a large cohort of MS-treated patients.

Methods: Cross-sectional study with collection of serum samples from 339 MS patients immediately before a scheduled rituximab infusion. ADAs were detected using an in-house-validated electrochemiluminescent immunoassay and a commercial enzyme-linked immunosorbent assay (ELISA) to compare methods. Data on patient demographics and clinical outcomes were retrieved from the Swedish MS Registry and patient records.

Results: ADAs were detected in 37% of relapsing-remitting MS and 26% in progressive forms of MS. Presence of ADAs decreased with increasing number of rituximab infusions. There was a significant association between both presence and titres of ADAs and incomplete B-cell depletion, but not with infusion/adverse reactions or clinical outcomes at the group level. Only five patients terminated rituximab during follow-up, four of which were ADA positive.

Conclusion: Rituximab treatment is associated with a high degree of ADAs, which correlates with efficacy of B-cell depletion; however, the clinical relevance of ADAs remains uncertain.

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founding

I feel like time is not on his side, if he is eligible for the treatment but it has a cut off at 15yrs. I think I would begin the AHSCT process while I waited to see the MRI and OCB results, if he decided his other option was not safer.

Is cladribine also poor at preventing brain volume loss?

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founding

Sooo…is your thought that Cladribine, like anti-CD20s, would also be less attractive to people who are OCB-ve since it seems most of Cladribine’s positive effect is due to actions on B-cells? And what are the chances that OCB-ve folks might simply have b-cell involvement that is not the work of OCB/antibody emitting plasma cells in the CNS…meaning maybe, I dunno, memory B-cells pop-in in and out of the CNS from time to time emitting cytokines and doing some antigen presentation then bailing out thru the lymph ductwork? Thanks for any insight as I am contemplating options.

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