Ocrelizumab removing oligoclonal bands in a few people within one year

O

Whilst hunting through the ECTRIMS 2020 meeting I came across this presentation. We have made a hypothesis that ocrelizumab may act as an immune reconstitution therapy with long term-benefit form a short term treatment cycle. We don’t have the data because we don’t have the trial. The manufacturers have little incentive to do such a trial and neuros probably dont want to tread on the manu

P0110. Modulation of cerebrospinal fluid immunoglobulins by ocrelizumab treatment
M. Weber et al.Background: Intrathecal production of immunoglobulin (Ig) and the presence of cerebrospinal fluid (CSF)–specific oligoclonal bands (OCBs) are hallmarks of multiple sclerosis (MS) that persist throughout the disease course and treatment. Objectives: To describe baseline (BL) correlations of CSF IgM and IgG production with CSF biomarkers and to assess the pharmacodynamic effects of ocrelizumab (OCR) treatment on these parameters in patients with relapsing MS (RMS) from the Ocrelizumab Biomarker Outcome Evaluation (OBOE) study (NCT02688985). Methods: Seventy-nine of 100 total patients with RMS had available BL CSF samples for assessment of IgG OCBs, IgG and IgM (measured at University Medical Center Göttingen), with demographic, MRI and clinical parameters representative of the total RMS population. CSF samples at either 12 (n=22), 24 (n=24) or 52 (n=17) weeks postdose and from a 12-week reference arm (no OCR; n=16) were assessed for longitudinal changes. Results: Median (interquartile range [IQR]) CSF levels at BL were as follows: IgG index, 0.79 (0.63–1.28); IgM index, 0.19 (0.11–0.33); CD3+ T cell number, 2.52 (0.80–5.61) cells/µL; CXCL13, 9.89 (3.91–31.50) pg/mL; CCL19, 47.95 (31.09–70.86) pg/mL; neurofilament light chain (NfL) 1280.0 (828.1–2968.9) pg/mL. At BL, IgG index and IgM index correlated moderately with levels of B cells (r=0.65, r=0.4 respectively), T cells (r=0.54, r=0.3 respectively) and CXCL13 (r=0.58, r=0.43 respectively), but not CCL19 or NfL. IgG index tended to decrease with OCR treatment and was significantly reduced by 52 weeks (n=17/79; median [IQR] change from BL −9.5% [−20.4% to −0.1%]; p<0.02) compared with stable levels in the reference arm. While IgG OCBs were detected at BL in all patients, IgG OCBs tended to decrease with OCR treatment, with three of 17 patients having no detectable IgG OCBs at 52 weeks. Reductions in IgM index were not observed with OCR treatment. Conclusions: Baseline CSF levels of B cells, T cells and CXCL13 correlated with IgG index and to a lesser degree IgM index in patients with RMS from the OBOE study. Significant reductions were observed in IgG index with OCR treatment, along with a trend toward reduced OCBs, with three patients showing no detectable OCBs. These data suggest that OCR impacts CSF Ig production, a hallmark of MS not previously thought to be affected by B-cell depletion therapy. These 1-year observations need to be confirmed with longer-term data and correlated with clinical response

Disclaimer: Please note that the opinions expressed here are those of author and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

See comments from Prof Freedman

“Sometimes Ig levels can fall below the level of detection in gels used to determine OCB. Therefore lack of detection with a low Index might not mean absence of banding. We have observed the same in our HSCT patients who, 3 years out had very low Ig levels and OCB no longer could be resolved”.

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20 comments

  • Sometimes Ig levels can fall below the level of detection in gels used to determine OCB. Therefore lack of detection with a low Index might not mean absence of banding. We have observed the same in our HSCT patients who, 3 years out had very low Ig levels and OCB no longer could be resolved.

    • “We have observed the same in our HSCT patients who, 3 years out”

      How many…what percentage of your HSCT patients..?

      Why did it take 3 years after hsct but only a year of Rituximab for the 3 out of 17 mentioned here..?

  • MD,

    “three of 17 patients having no detectable IgG OCBs at 52 weeks”

    What does this mean ie if an MSer no longer has OCBs? Would an MSer with no OCBs still experience relapses or smouldering MS? Apologies for the Mickey Mouse question, but I’m confused as to what it actually means (I think it’s an aim of the SIZOMUS trial if I’m not mistaken).

    Have a good weekend. Pubs open properly on Monday so I’ll see you in The Brewery Tap at midday.

    • If you are buying I’ll be there… as I wouldn’t mind a pint

      What does this mean….is a good question and the answer is I dont know, because it seldom happens I believe. One view would be this is a marker of undesirable activity and maybe getting rid of them would be beneficial…This is a hypothesis

    • “What does this mean ie if an MSer no longer has OCBs? Would an MSer with no OCBs still experience relapses or smouldering MS? ”

      Cured. Pender calls OCB multi-clonal b cell expansions in the CNS

      Google: soundcloud NCTalks at AAN 2017 Pender EBV

      “Elucidating the characteristics of B cells that populate the MS CNS, how they traffic into the CNS and how they may contribute to progressive forms of the disease has become of considerable interest. Here, we will review characteristics of human B cells identified within distinct CNS subcompartments of patients with MS, including the cerebrospinal fluid, parenchymal lesions, and meninges, as well as the relationship between B cell populations identified in these subcompartments and the periphery.”

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689808/

  • Nice post

    So no Ocb equal no plasma cells producing antibodies in the brain

    Would like to know if those patients get better

    Does O gets in the brain after all?

    Or just in some patients ?

  • “with three of 17 patients having no detectable IgG OCBs at 52 weeks. ”

    Why only 3..were they the most recent diagnosed..?
    Why has Sweden not found this out..?

  • Results: After a median follow-up time of 745 days, immunoglobulin G (IgG) OCB remained detectable
    in 74% of patients, the proportion of patients with a pathological IgG index went down from 70% to 46%,
    and the proportion of patients with a pathological NFL went down from 72% to 24%. In patients with
    follow-up time >1500 days, IgG OCB were detectable in 50% of patients, 14% had a pathological IgG
    index and none a pathological NFL.
    Conclusions: Intrathecal immunoglobulin production and NFL were lower after treatment with aHSCT,
    decreased over time and were normalised in a significant portion of patients. This challenges the notion
    that OCB are unaffected by therapeutic intervention in MS.

    Intrathecal immunoglobulins and
    neurofilament light after autologous
    haematopoietic stem cell transplantation
    for multiple sclerosis

    Well it would be nice to see if after more than one 1 year (to 3 4 or 5 years ) more patients get ocb negative

    It seem with time ocb´s tend to fade away at least in some patients in the hsct cohort

    https://pubmed.ncbi.nlm.nih.gov/31347948/

  • Why OCB are still measured by gel electrophoresis instead of capillary? I think it is much more sensitive and it should prevent false negatives

  • Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study: https://pubmed.ncbi.nlm.nih.gov/30368223/

    Let’s not forget about the positive therapeutic effects of Cladribine. Recently, Prof G. seems to be on a Alem/aHsct campaign and he never includes Clad in his…..closing thing to a “cure” discussion.

    Maybe we could get a status update on some of Prof. K’s endeavors with Clad?

    • Not true; I discuss the ORACLE or CIS studies and argue of cladribine to be available to use early. The problem is we have no long term data on cladribine and the BVL data from the CLARITY trial was disappointing.

      • I qualified my statement with “recently” 🙂

        I know you are a big supporter of the early and effective approach.

  • Chinese MS clinics do a lot of lumber punchers. On average pwms in China would go through 2+ lumber punchers, 1st at the first hospital when one go-to when symptoms onset, 2nd at a more MS-specific hospital, 3rd, at one of the best MS centre in China (Shanghai/Beijing/Zhejiang), and 1b 2b if one were not diagnosed as MS straight away. No hospital don’t like to take tests from other hospitals. A friend of mine did 3 lumber puncher within the first 6 month of onset of symptoms. The first hospital couldn’t diagnose MS (1a), and she went to the second one got diagnosed (1b), and then went to a hospital with a stronger MS department (2).

    Anyway my point is Chinese MS centres have a lot of CSF data for each patient, and I was told even without DMT treatment, the OCB bands come and go. Few hypotheses 1. Something to do with Asian MS subtype has fewer OCB prevalence (was reported ~30%-80% from various studies in China/Japan, compared to 90%+ from western countries); 2. Temporary suppression of OCB bands from Corticosteroids treatments, the CSF was taken after having corticosteroids; 3. OCB bands fluctuate in some Asian patient, fades quickly after a relapse? Plasma Cells of these group in CNS have short lives?

    Do Plasma cells have to reside in bone marrows to live long? Can they stay in CNS and live long or they have a way to reproduce? Or they circulate from bone marrows to CNS in a way?

  • Hi MD, thank you for this post and it is especially interesting to me as I’m on Ocrelizumab as we speak! My next infusion is due in July and it is always good to start ‘pumping me up’ to get to the point of the cannula being inserted, they have to find a specialist to insert it – as my veins don’t play ball anymore! Then to sit for 6 hours attached to the drip and sharing the space with chemotherapy patients, to feel that I’m doing the right thing with this treatment and my MS is being kept at bay! So to have a build up of positivity around this treatment and for everyone to take on these findings, regardless of who you upset, rattle or shake to move forward with further trials and potentially helpful, dare I say on the way to curing, or at least for some, stopping the disease attacking further, then you have to dig further and raise this with the people who can allow further investigation. Otherwise, we seem to go round in a pharma loop of more great medications created (of course, this is good) but more study with patients already on treatments to see how the drug is working, or not, and make a change as soon as possible. There is a lot of talk about lessening the doses and depending on how long you’re on the drug, to giving breaks. How long can you be on Ocrelizumab and how long before your body fights back and can’t take anymore (individual I know)? Also, just for the record, why are some people given a diagnosis of MS without having a lumbar puncture? I was advised that I needed a LP to ensure a clearer diagnosis – and I have mentioned before (dramatised in another post) that it was a horrendous experience and the pain I went through with this procedure, I wouldn’t wish on my worst enemy, or would I 😉 So, how do those poor patients in China have to go through that procedure, more than once! Probably offered full-out sedation – and boy I would opt for that, if I needed to have another one!

    • You will be please to know that they are doing a trial with subcutaneous infection so I guess a minute and an hour wait to ensure no side effects.

      Why are some people given a diagnosis of MS without having a lumbar puncture? Neuro or PwMS doesn’t like LP’s
      As for Lps it is important that you do not use a cutting needle (Quinck) but a non cutting needle (Sprotte) to reduce head aches for one of our trials people did 4 and in Sweden LP’s are used.

      You long can you be on ocrelizumab…according to pharma this would it forever, I doubt this based on the Swedish experience we are meeting with them soon to learn from their experience

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