ProfG has hope

P

ProgG is giving a rallying call, let’s hope he is correct and that people buy into the idea. However it is clear that this is no quick fix and to think that you get it right first time, is also a concern, because if you get it wrong is there the chance for another go. For example Epstein Barr Virus (EBV) RNA vaccines have been made and they are only designed to prevent infection, but are unlikely to get rid of the hidden virus. But if you don’t start you can’t fail.. However you have a biomarker toknow if the strategy works and that is blocking glandular fever. Will it then be associated with reduced autoimmunity….I would argue that it is more thanjust MS…bt I guessit depends on how you look at what EBV is doing. Here is an abridged copy of the content.

ONSET OF MULTIPLE SCLEROSIS IS PREVENTABLE – TIME TO ACT NOW! Hawkes CH, Giovannoni G, Lechner-Scott J, Levy M, Yeh A. Mult Scler Relat Disord. 2022 ;62:103875. doi: 10.1016/j.msard.2022.103875.

It is generally acknowledged that relapses in multiple sclerosis (MS) are significantly reduced by the latest selection of immunotherapies, especially those that target CD20. The progressive forms remain a challenge and preventing the onset of MS has not been achieved.

There is abundant evidence that exposure to Epstein Barr virus (EBV) is universal in those with MS . Raised serum antibody titres against EBV nuclear antigens (EBNAs) and the presence of EBV in MS demyelinated lesions are reported in most pathological studies. In fact, someone who is EBV-antibody negative, probably does not have the disease. A past history of infectious mononucleosis (glandular fever) and the main MS risk gene increases the risk of MS by ∼10 fold

It was shown that there was a 32-fold increased risk of MS in those who had prior exposure to EBV within the previous 7.5 years (on average). This figure represents the highest known MS risk for any proposed MS aetiological factor. This evidence, combined with the fact that CD20 monoclonal antibodies that target B-cells, a primary site for latent EBV infection, are highly effective, makes the case for EBV infection as necessary, if not sufficient, to cause MS. Even assuming that EBV is merely in the causal pathway, cutting the chain, by for example, a vaccine, should prevent MS.

So what next? Public health measures to discourage the exchange of saliva and other body fluids directed at susceptible groups, namely adolescents, seem obvious but likely impractical. Could targeting EBV with antiviral agents be a solution? Antivirals could be tested in people with MS and importantly, offered to those with infectious mononucleosis, which occurs typically during adolescence or early adulthood. Antiviral agents, however, would need to target both lytic (exploding cells to release content including new virus particles) and latent (hidden from the immune system inside cells ) EBV infection. At present, there is no licensed antiviral agent for treating EBV, although rituximab (anti-CD20) is widely used and effective for EBV-associated lymphoproliferative diseases. The aim of an antiviral agent would be to ‘sterilize’ the body of EBV, but this may not be possible, or if it were, it might only be short-lived. Better still would be a large-scale prophylactic vaccine programme, which could be given early in life to prevent primary EBV infection.

Hitherto, progress in the domain of EBV vaccine development has been slow and fraught with technical issues but advances have now been made, in part stimulated by the need to develop vaccines against SARS Cov-2. There are a number of potential approaches

Fig. 1

This would just be the start…..What would be the best time to vaccinate given that 70% of those aged 1-5 years are seropositive for EBV? Is there a case for adding an EBV vaccine to the usual 6-in-1 / rotavirus / meningitis B vaccines offered to UK infants aged 8 weeks? Should we offer an EBV vaccine only to EBV negative individuals? Should a vaccine be offered to those with MS to enhance their passive immunity?

Another concern with most vaccines is that they do not necessarily guarantee life-long immunity. Thus, primary EBV infection may be postponed into middle age resulting in severe glandular fever and subsequent late presenting MS. Thus a booster vaccine would be needed to counter such risk.

A vaccine for EBV-seronegative adolescents is a major unmet health need. We now have technology that has the potential to eliminate MS once and for all. If we assume 5 years for vaccine trials followed by the administration in the first instance to all children ag ed say, 12-18 years, then EBV infection and subsequent adult-onset MS should be abolished.In other words, adolescent-onset glandular fever should gradually fall to zero from 2028 onwards followed by a marked reduction in subsequent MS over the ensuing decade. Whoever achieves this first will rightly receive the highest medical accolade of the 21st century.

Disclaimer these are the view of the author

Post-alemtuzumab Graves’ disease remitting after switch to ocrelizumab.Popescu V, Beirinckx A, Decallonne B.Acta Neurol Belg. 2022 . doi: 10.1007/s13760-022-01962-9

Alemtuzumab is used for active cases of multiple sclerosis (MS), typically administered in two yearly courses. The most frequent long-term side-effect is secondary autoimmune thyroid disease in 35–40% of people where this manifests as Graves’ disease (over active thyroid gland) in about 70% of people, characterised by antibodies against the thyrotropin receptor, requiring antithyroid drugs or therapies such as radio-iodine or removal of the thyroid gland. Anti-CD20 monoclonal antibody, is also used for the treatment of active MS…. A case of an MS patient who developed clinically and biochemically overt alemtuzumab-induced Graves’ disease, remitting 6 months after treatment with ocrelizumab and methylprednisolone pulse-therapy. This case highlights the possibility of treating both autoimmune diseases with methylprednisolone pulse-therapy and ocrelizumab.

We have heard of the Texan “Whack a Mole” approach where by you bash B cells with CD20 depleting antibodies as the B cells recover to stop anti-body related autoimmunity occuring as a side effect. The problem with that approach is that you could be whacking forever and you whack the worms and the ground feeding bird and other innocent creatures and you then kill the moles that aren’t ruining your lawn. It is evident that the cells that come back after depletionare not the same as before, so you needlessly beat the ground forever. We have made the suggestion that you dont have to treat with ant-CD20 forever to treat MS,and I would argue that this view has yet to be disproved as is supported more and more. After alemtuzumab you can get antibodiy-mediated side-effects. Although anti-CD20 do not target the antibody producing cells there are plenty of examples whereby rituximab (anti-CD20) is used successfully in antibody-mediated disease, so is it surprising that benefit can be had using anti-CD20 after alemtuzumab to control MS and the drug-induced side-effects. The question is why would ant-CD20 work when anti-CD52 (alemtuzumab) did not?. Maybe it is the CD52-negative cells that develop after alemtzumab that are invisible to alemtzumab but not ocrelizumab or maybe alemtuzumab wasstill working and rather than 1 lesion prompting the switch would have been 20 lesions had it not been teated.

This observation should be simple to repeat and you may have youronw personalexperience.

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19 comments

Leave a Reply to Richard Alan Woods Cancel reply

  • Lol, how do you switch to a maintenance DMT from an IRT. More likely disease reactivated + graves and Ocrelizumab made sense?

  • I’m looking forward to accessing this one! I may be in a similar situation post-Mavenclad, and I spent the weekend puzzling it out. Because EBV is hosted in CNS AND epithelial tissue, treatments only clean out B mem cells so I believe it’s possible to get reinfected eventually from the epithelial stored EBV. Reinfection drives progression in my case.

    Solutions are in the works, for which I’m thankful. I’m leaning towards an anti-viral again, but do wish some of the pipeline treatments like ATA188 were farther down the line!

    There seems to be a relationship between Graves and EBV – quite a number of hits. So treatment with Ocrevus will take care of the damaged b mem cells.

    https://journals.viamedica.pl/endokrynologia_polska/article/view/EP.2015.0020/29453#:~:text=Introduction%3A%20Autoimmune%20thyroid%20diseases%2C%20including,environmental%20factors%20involved%20in%20autoimmunity.

  • Do I have to pay for this article to be able to read it? – ‘Onset of MS is preventable’

  • Any thoughts on using Ixazomib and a mild anti CD20(like Ofatumumab) together? Could this be very effective mid and long term or maybe too dangerous? Just your personal opinion o the role of plasma cells in MS and what this could do, I know it’s all theoretical …

    • (a) Not sure I agree ofatumumab is a mild anti-CD20…after a few rounds it will get more potent as it clears B cells out…But this is made by Novartis andocrelizumab is made by Roche
      (b) Ixazomib is a proteosome inhibitor made by Takeda.
      Therefore unless the two companies do adeal this won’t happen. NDG is doing a trial in MS (SIZOMUS) as we speak….This aget can get in the brain to clear B cells (based on studies with B cell cancers) ofatumumab is not going to get in the brain…so not a bad idea.

  • “In other words, adolescent-onset glandular fever should gradually fall to zero from 2028 onwards followed by a marked reduction in subsequent MS over the ensuing decade. Whoever achieves this first will rightly receive the highest medical accolade of the 21st century.”

    Looks like Prof G is angling for a Nobel Prize. Unfortunately he’s not exactly Speedy Gonzales when it comes to taking ideas to something available at Superdrug.

    Prevention is crucial, but stopping MS (the real MS / smouldering MS) in people already with it will benefit the millions with MS around the world. Wouldn’t it be nice for a neuro to tell an MSer that there is a treatment which can stop any further deterioration? This would give MSers hope and a bit of job satisfaction to a neuro.

  • Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity:

    Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing–remitting multiple sclerosis; however, the high risk of secondary auto- immune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary auto- immunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients be- fore and after alemtuzumab treatment focusing on those critical time points.
    Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periph- ery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signa- tures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease.
    In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mir- rored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contrib- ute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity.

  • “If we assume 5 years for vaccine trials followed by …”

    Why 5 years?
    Now that we have seen that vaccine can be developed and administered much faster

    “Should a vaccine be offered to those with MS to enhance their passive immunity?”
    How much do we know or what is the best guess for this question?
    Will targeting EBV help those who have MS already?

  • There is yet another therapy against viruses: Supportive Oligonucleotide Therapy SOT. SOT inhibits the expression of proteins that are essential for cells metabolism and /or survival. Basically it blocks the gene responsible for multiplication.
    I have had that against HHV-6 (once, disappeared), VZV (once with diminished viral amounts), EBV (thrice, with diminished lytic and latent amounts and finally IgG inside the scales). I’ll be checking the EBV situation again after the summer, and then determine whether another SOT is needed. My goal is to get rid of EBV and then see what is the state of my MS.

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