What about Atrophy?


ProfG has thrown the T and B curve ball by suggesting that brain atrophy data is better with the T and B depleters (Alemtuzumab and HSCT) than the relative B depleters (Ocrelizumab and cladribine).

This is an interesting observation and if correct it needs to be brought into the MS World View. This may point the finger at CD8 T cells as this subset deleted less than CD4 by cladribine and is dominant in MS lesions and are depleted by alemtuzumab and HSCT but not ocrelizumab

So as the Maven lands the first comment posted says “What about atrophy?”

The atrophy data in the CLARITY trial is admitedly not that great with a rate of about -0.56% brain loss a year (De Stefano et al. Mult Scler. 2018;24:222-226). If this is compared to years 1–5: −0.48%, −0.22%, −0.10%, −0.19%, −0.07% with alemtuzumab in the CARE-MSI (Havrdova E et al. Neurology. 2017;89:1107-1116). After the first year it doesn’t look that great. Normal aging is about 0.1-0.2% brain loss a year.

However, I have said previously that the people in the CLARITY trial had MS for on average 9 years verses only 2 years in the CARE MS-I trial. It is well known that in the first year of many DMT there is seeming shrinkage because the loss of inflammation, leading to loss of swelling.

So I went back to the ORACLE study where people with first symptom was given the cladribine tablets where the mean duration of disease before treatment was 0.2 years. There was no data in the paper that I could remember.

However, when I had a look in the (unpublished..well sort of) supplementary trial data. The licenced 3.5mg/kg dose was -0.48% at years one and do the maths -0.2% at year 2. If you look at the higher dose it is -0.1% at year 2. Admittedly the year 1 and year 2 groups are not matched and the data needs to be properly re-analysed

However, my thesis that they all work the same is now still standing and the atrophy data looks comparable to me. Head to head studies needed but probably won’t happen.

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  • But cladribine affects also T cells… Not at the same extension as alemtuzumab but it does. Perhaps the right comparison should be to ocrelizumab.

    • No, not at all. I would like to know if T depletion in clad is good enough. If it is, there is no need to use Alem at all, as it has MUCH more severe AEs… We already know that Ocrelizumab/Rituximab is not enough for a lot of people (just remember a citation that ProfG reported from Swedes that a lot of their patients on Rituximab progressed to SPMS).

      • But where is the data. If prof Hauser has compelling data and he is not reporting it it would be a soory state of affairs and would make you ask if because he is in bed with Roche. A sad state of affairs.

        The Swedes will give us the answer and if stuff is being hidden the ProfH should get a free ride from San fransico to Coventry. The truth comes out.

        • Amen, MD! Thank you for speaking honestly on this. As someone on ocrelizumab, it’s very disconcerting to see anecdotes from Dr Hauser and others suggesting bad news that is not being publicly shared. If there’s data, they have an obligation to publish. Until then, I have to assume it’s hogwash….

        • Sorry to say researchers are now more inclined to behave in the interests of pharma. Given the retreat of government research grants and total strangle hold of pharma on research. So yes if Dr Hauser is in bed with Roche. Do not shoot the messanger. Get him to do a guest post and explain himself on why he no longer thinks b cell is the way forward.

          • “explain himself on why he no longer thinks b cell is the way forward.”


            he speaks………..:(

            “We demonstrate complex patterns of clonal B cell persistence in CSF and blood, even in patients on immune-modulating therapy. Our findings support the concept that peripheral B cell activation and CNS-compartmentalized immune mechanisms can in part be therapy resistant.”

          • Yes good answer, however I believe this would be the same response for alemtuzumab and therefore the rate of conversion to progression would be no different. That is the point I would make

            If the immune response in the brain gets established progression is occurring and even HSCT will probably not stop it. So again it depneds when you start treatment

          • “We already know that Ocrelizumab/Rituximab is not enough for a lot of people”

            Anders Svenningsson from the COMBAT-MS trial in Sweden (where they believe that by preventing lesions it can prevent SPMS -but they still wait for the data, so it is still a theory) says that when a patient has been in the disease for years when he starts RTX, it doesn’t prevent them from progressing to SPMS.
            So right there you can have a trial to compare if Alem./HSCT or Maven. can stop the progression of these older RRMS patients, who we know will progress to SPMS with RTX (or O.).

            The Swedes are ongoing a phase 3 trial with RTX that will give some data on brain atrophy rates.

      • Longitudinally persistent cerebrospinal fluid B cells can resist treatment in multiple sclerosis

        “Our findings raise the possibility that IMTs, which effectively reduce clinical and MRI relapses, may not sufficiently target CNS-compartmentalized immune mechanisms that have been associated with gradual and relapse-independent MS worsening in relapsing MS and progressive forms of the disease (48). Effective targeting of CNS-compartmentalized inflammation may, in the future, achieve efficacy in progression slowing superior to that of current therapies (2). Longitudinal immune repertoire studies performed alongside the clinical development of such potentially novel MS drugs may well provide critical immunological and biomarker evidence indicating the successful suppression or elimination of progression-driving mechanisms”


        • None of those patients received anti CD20 treatment- none of them were on Alemtuzumab. No depleting therapies at all- just migration inhibitors. Oh and interferon 🙁 What relevance does this paper have on the B cell depleting therapies? This is a poster in paper form.

          • “None of those patients received anti CD20 treatment- none of them were on Alemtuzumab. ”

            Huh..we’re talking anti-CD20 are we not.
            As for Alemtuzamab no-one gets it first line in U.S. Aaron
            Boster in his video
            says he has tried but always denied by insurance co.
            And if he can’t no-one in U.S. can.

    • Clad depletes CD4 cells by about 30-40 percent and cd8 by about 10-20percent not enough for major relapse effect. Ifyou know of ocrelizumab data i will report it but i have already shown rituximab data at 0.2percent

  • OK nice one MD. Finally there is response that’s based on data and not just anecdotal assumptions on disease duration. Will be interesting to read Prof G response. I suspect he may have a counter argument.

  • Does cladribine have an impact on brain atrophy in people with relapsing remitting multiple sclerosis? November 2017

    In the first six months, PBVC is lower in the placebo group, likely due to pseudoatrophy. Then, instead of using the brain volume from timepoint “6 months” as a starting point to calculate PBVC for period (b), the authors set the starting brain vol-ume back to zero and calculated PBVC thereafter. At 24 months, both cladribine arms seem to be superior over placebo, with a PBVC for people treated with cladribine tablets 3.5 mg/kg of −0.77% (±0.94%, p = 0.02, n = 336) and 5.25 mg/kg of −0.77% (±0.95%, p = 0.02, n = 351) compared with those treated with placebo −0.95% (±1.06%, n = 338).However, when looking at the whole time period and adding up the percentages depicted in Figure 1a and 1b in the paper, cladribine and placebo do not significantly differ in PBVC at 24 months (placebo: –1.15%, cladribine: 3.5 mg/kg –1.2% and 5.25 mg/kg –1.2% PBVC; see an estimation in Figure 1 in this letter). (Please note that our calculations are only estimates. In the paper, brain volume at 6 months is used as a reference point to calculate PBVC for period (b), when applying baseline brain volume these numbers will differ slightly.) The pro-cedure to split data due to expected pseudoatrophy was not used in similar papers investigating PBVC after immunotherapy with, for example, natali-zumab,2 daclizumab3 or fingolimod.4On a different note, Sastre-Garriga et al. found that the presence of gadolinium enhancing lesions at baseline affected brain volume change in the first and second year, but not third year of treatment with natalizumab. Therefore, they suggested that pseudoatrophy might occur for up to 2 years, which renders a division at 6 months debatable.
    In conclusion, from our understanding, the data pro-vided in the paper of Stefano et al. (CLARITY) do not prove a reduced brain atrophy rate by cladribine. We propose that the effect of cladribine is re-calculated on PBVC using the data from the whole treatment period, base-line to 24 months.


  • I’m convinced Brain Atrophy is finally what matters most
    But I’m totally confused about the evidence regarding brain atrophy

    Prof G seems convinced Anti-CD20 is not the best treatment in this respect, apparently because of something Prof Hauser said orally
    Mouse Doctor seems to have other views

    Now what??

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