Will the Sh1 Stick?

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As you may realise that I have been abit of a CLAD-lad in the past, but it is clear that this is a mis-understood drug. People don’t understand how it works, yet it is re-assurringly simple to explain. Importantly I think neuros run scared as soon as you mention cladribine, because as the saying goes the “SH1 sticks

Cladribine now carries the baggage of the the occurrence of cancer, because in the pivotal trials were there were none in the placebo group but about 3-6 (depending on how you see it ) in the cladribine groups. So this is the legacy. Even if you do work to show this is no different from other agents and the trial result was a fluke…the bow-tieds neuro brigade have made their mind up to steer-clear and is used to justify their use of the low-efficacy CRAB drugs

Ocrelizumab has been a bit more teflon (non-stick coating) and despite a much higher occurence of cancers in the trials than occurred with cladribine, the regulators in contrast did not bat an eyelid, maybe because there was data from three trials not one.

So ocrelizumab flew high and became a popular high-efficacy drug. However, COVID-19 has come along and attention has now been focussed on the attributes of ocrelizumab. The SH1 has hit the fan and anti-CD20 depleting antibody apparently doubles your risk of developing COVID-19. Is this the SH1 coupled with vaccine concerns that will stick and influence your decision to prescribe or to use an anti-CD20 antibody?

What does a doubling of risk mean? Is it 1 in a million chance going to 2 in a million? or 1 in 10 going to 2 in 10?. In the UK the figures suggest that 0.5% have been infected. The figures are clearly wrong as it is based on the woeful level of testing. However, is it really a doubling. If you accept that 50-80% of people infected are asymptomatic it is possible that infection risk has not changed by whether you show symptoms has.

It is unlikely that taking ocrelizumab/rituximab is going to change your behaviour to increase the chances of getting infected, I suspect the opposite is the case that you will be more cautious. But what about the biology to explain the risk

The COVID-19 dilema for ocrelizumab and rituximab is a product of success as data is key and because of the popularity of anti-CD20 depletion therapy, there are lots of data.

With rituximab and ocrelizumab, you deplete B cells and this inhibits B cells that drive active MS. The T cell immunologists say it works because it blocks antigen presentation, so now it gives you the problem for COVID-19 as you can’t have it both ways

  1. Ocrelizumab blocks presentation of antigens to T cells therefore you do not make a T cell response. Therefore you will not make an fully effective anti-COVID-19 response. We believe that anti-T cell responses are important for defending against COVID-19. This will increase your chance of being symptomatic. Now I would argue that priming immune responses are a product of other immune cell types like dendritic cells but we are only talking less than doubling the risk and so it is not a massive impact.
  2. Depleting naive B cells blocks your capacity to may new antibodies, so perhaps, if you get COVID-19 your ability to remove it is blunted because you cannot make anti-SARS-CoV-2 IgM, (IgA) and IgG responses as effectively because the naive B cells are not there to respond to the infection.
  3. IgM is the first line of antibody response against infection. If you are on long term anti-CD20 treatment it depletes your levels of IgM such that within 5 years they are reduced by a median of about 55-60%. Anti-IgA and IgG is depleted by about 20%. Importantly the IgM response drops pretty quickly and is down after a few infusions. Therefore it is not there to fight infection
  4. IgA is another antibody response that occurs shortly after symptom on set. This response is blunted. It is evident that delayed IgM and IgA responses are associated with more severe COVID-19.
  5. It appears that past exposure to cold-causing coronaviruses protects you from covid-19 as you make protective T and B cell responses. So with long term treatment your levels of antibodies drop and therefore the protective antibody levels will stop but………………………..
  6. if you encounter the virus when on treatment you may not make an protectivre T cell responses because of (1) and the protective B cell response because of (2).

Can you add more possibilities

These risks are simple biology and will apply to other viruses too. Isn’t it time to do a study that explores whether you have to take CD20 depletion for ever. I suspect you don’t need to but maybe the SH1 hititing the fan will encourgage someone to do a formal study, such as the ADIOS study to try improve safety of MS treatment.

The ocrelizumab phase II extension trial suggests the potential to improve the risk: Benefit balance in multiple sclerosis.Baker D, Pryce G, James LK, Marta M, Schmierer K.Mult Scler Relat Disord. 2020 Jun 8;44:102279. doi: 10.1016/j.msard.2020.102279

COI:Multiple

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MouseDoctor

4 comments

  • Thanks MD!

    I thought T cell immunity was pretty much intact on anti CD20 and as the first line of defence against covid that was one of the saving graces? Point 1) seems to suggest otherwise?

    • Yes you are correct the T cell should be pretty much intact, but it is not the first line of immunity, I think it is the second or third line. One question is, is point 1 correct….the T cell biologists suggest this is the way that CD20 works in MS. I am not so sure. The argument in point 1 was made from blocking CD4 T cells which is associated with MHC class II antigens. Is this argument correct for MHC class I which stimulated CD8 T cells

      I’ll have a look
      So good news if this paper is correct and approrpriate:
      A Specific Role for B Cells in the Generation of CD8 T Cell Memory by Recombinant Listeria monocytogenes
      Hao Shen, Jason K. Whitmire, Xin Fan, Devon J. Shedlock, Susan M. Kaech and Rafi Ahmed
      J Immunol February 1, 2003, 170 (3) 1443-1451; DOI: https://doi.org/10.4049/jimmunol.170.3.1443

      In this study, we investigated whether B cells play a role in the induction and maintenance of CD8 T cell memory after immunization with an intracellular bacterium, Listeria monocytogenes. Our results show that B cells play a minimal role in the initial activation and Ag-driven expansion of CD8 T lymphocytes [SO POINT 1 is NOT RELEVANT HERE]. However, absence of B cells results in increased death of activated CD8 T cells during the contraction phase, leading to a lower level of Ag-specific CD8 T cell memory [SO POINT 1 IS RELEVANT HERE]. Once memory is established, B cells are no longer required for the long-term maintenance and rapid recall response of memory CD8 T cells [SO POINT 1 is NOT RELEVANT HERE] . Increased contraction of Ag-specific CD8 T cells in B cell-deficient mice is not due to impaired CD4 T cell responses since priming of eptiope-specific CD4 T cell responses is normal in B cell-deficient mice following L. monocytogenes infection [SAYS THE T CELL IMMUNOLOGISTS IN MS ARE TALKING RUBBISH]

      While it is generally accepted that B lymphocytes can present antigen and activate CD4 T cells, priming of CD8 T cells by B lymphocytes remains controversial. Recently, we
      showed that mice injected with genetically programmed B lymphocytes generate antigen specific CD4 and CD8 T cell responses in vivo that could also be induced in mice
      lacking functional dendritic cells [SAYS POINT 1 IS VALID]. To gain further insights into the requirements for T
      cell priming by antigen-presenting B lymphocytes, in vitro experiments were performed using ovalbumin (OVA) and OVA-specific TCR-transgenic CD4 and CD8 T cells. We
      found that while B lymphocytes can directly prime CD4 T cells, the activation of CD8 T cells requires T cell help [SO POINT 1 IS VALID]. The effect of activated CD4 T cells can be replaced by
      soluble recombinant IL-4. Collectively, the data show the existence of different requirements for priming of CD4 and CD8 T cells and point to the previously unappreciated fact that the induction of CD8 T cell responses by B lymphocytes requires T cell help.

      Another study
      Both CD4+ and CD8+ T-cell activation was unimpaired by B-cell deficiency [POINT 1 IS IRRELEVANT]

      So it is not quite clear

  • As alway, thank you for sharing your insights MD! I have been monitoring my lymphocytes monthly since stopping an anti CD20 agent eight month ago. B cell are still depleted, as expected, and may never come back😉. Interestingly, my T cells have been steadily increasing since my last infusion. It is amazing to watch how these DMTs mess with ones immune system.

  • A question about colds in general:

    We all feel miserable for a few days when we get a cold.
    Is the miserable feeling a direct result of what the cold virus does?
    Or is it because our bodies are fighting the cold virus?

    Reason for the question:
    Most people suffer a cold at least once a year I guess. But the family member on rituximab (for years) doesn’t seem to get any colds. Others in the household do.

    Is this a coincidence, is it because of a better ability to ward off the cold virus, or is it that her body does NOT fight the virus?
    Or some other reason?

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