Journal Club: whack-a-mole


The latest Barts-MS journal club describes and discusses the Whack-A-Mole strategy dealing with secondary autoimmunity post-alemtuzumab treatment. It is based on the paper below.

Meltzer et al. Mitigating alemtuzumab-associated autoimmunity in MS: A “whack-a-mole” B-cell depletion strategy. Neurol Neuroimmunol Neuroinflamm. 2020 Aug 7;7(6):e868. doi: 10.1212/NXI.0000000000000868.

Objective: To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyper-repopulation (defined when the return of CD19+ B cells approximates 40%-50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity.

Methods: In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50-150 mg/m2), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy.

Results: Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed. Conclusions: An anti-CD20 “whack-a-mole” B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation.

Classification of evidence: This study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases.

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The MS Bloggger


  • I may have misunderstood but I was following the VirtualMS tweets yesterday, and I thought that someone linked to a talk where it was said that increased B cells do not appear to explain secondary autoimmunity when using Lemtrada.
    See, MD and Doc G – we needed you!

    • If you low at B cellsand then look at autoimmunity 5 years later is it surprising thereis not relationship…..However if you look at the “tour de Force Tweets” from VirtualMS you ask “What have you been reading?”

      • I know, I know – I shouldn’t always* believe what I see on Twitter! Apparently this doctor was paraphrasing something that a prof who works in a certain UK university city said…

        I probably just misunderstood.

        *almost never

  • Good discussion, definitely share the concerns about the quality of the evidence.

    Don’t share the concern that patients wouldn’t deal with the treatment burden – if this actually worked, I would easily sign up.

    Less sure if I would sign up for a RCT though – plain alemtuzumab sounds like a risky proposal (though I am still unsure about the relative risk compared to HSCT).

  • Well look like your colleagues choose another route

    Pre-treatment with Natalizumab Reduces
    Risk of Alemtuzumab-Associated
    Secondary B-Cell Autoimmunities

    substantial risk for secondary b-cell-mediated autoimmunities
    (sAI). Hyperrepopulation of immature B-cells
    following administration is considered the substrate of sAI.
    Natalizumab (NAT) hampers the transmigration of
    lymphocytes into the brain but also shifts precursor B-cells,
    including autoreactive clones, from the bone marrow to the
    peripheral circulation, potentially making them a substrate
    for consequent ALEM depletion. We therefore hypothesise,
    that pre-treatment with NAT could prevent ALEM
    associated B-cell hyperrepopulation and sAI.
    Methods: We included 17 patients with multiple sclerosis
    switched from NAT to ALEM (NAT-ALEM cohort) and
    compared cell-surface and intracellular maker from
    peripheral blood mononuclear cells (PBMCs) measured by
    FACS to either a control cohort of 16 (natalizumab “naïve”)
    ALEM patients (nALEM cohort) or to the depletion rates
    from the CARE-MS-I.
    Results: NAT-ALEM patients had significantly increased
    (naïve) B-cell frequencies at ALEM start (baseline, BL)
    compared to nALEM controls. After 12 months, CD19+
    cells and naïve B-cells did not reach BL levels (-30%, -6%
    respectively) in the NAT-ALEM group, whereas they fully
    recovered in the nALEM group (+9%, +32% respectively).
    Moreover, the recovery rates of immature B-cells at month
    12 showed a discrepancy of about 120% (-31% vs. +90% in
    the CARE-MS-I study population). Most impressively, only
    2/17 (11,8%) NAT-ALEM patients developed sAI, in
    contrast to 50% in the control cohort.
    Conclusion: We show that pre-treatment with NAT appears
    to substantially lower the incidence of ALEM-associated
    secondary autoimmunities, most likely by making precursor
    B-cells, including autoreactive clones, accessible to a
    subsequent CD52 depletion.

  • I spoke with my wife’s neurologist about B cell driven (secondary) autoimmunity post alemtuzumab treatment and he wasn’t convinced. She now has Graves and her endocrinologist isn’t convinced either. Nobody has looked at her B cell count. I wonder if they did what they would find??

    Thanks for highlighting this article. Another piece of information to add to the puzzle.

    • I spoke to your neurologists and he wasnt convinced that the world isnt flat…..only joking
      Hind sight is a great thing

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