Barts-MS rose-tinted-odometer: ★ (Bank Holiday Monday morning  blues)

The next marketing battle in terms of MS DMTs will be herpes zoster and how we manage it. Shingles is quite common in the general population, but it is much more common in pwMS. Why? Probably because of the immunosuppression associated with MS DMTs and the use of high-dose steroids to treat relapses and prevent infusion reactions. Put simply Zoster comes with the territory of managing MS. The following figure is from a meta-analysis I have recently done on the rate of zoster reactivation on current MS DMTs relative to other DMTs and compared to what is expected in the background population. Do you find the results surprising? 

The two reported case studies below of severe shingles/herpes-zoster in two pwMS on dimethyl fumarate demonstrates two things. Firstly, contrary to what most people think DMF is an immunosuppressive compound. Even if we derisk DMF and switch treatments if the total lymphocyte counts drop below 880/mm3 or 500/mm3 there can still be quite a profound CD8+ T-cell lymphopaenia. Secondly, the cases below actually had relatively normal total lymphocyte counts despite low CD8+ T-cell counts. These cases make me wonder if we should be monitoring T-cells subset counts in our patients on DMF. 

The relative sensitivity of CD8+ T-cells to DMF must be a clue to how the drug is working from an immunological perspective. Despite this, the exact mode of action of DMF in MS remains a mystery. 

For several years I have been asking whether or not boosting cytotoxic CD8+ T-cell immunity against the herpes zoster virus with the new Shringex vaccine, prior to starting DMTs, would lower the risk of shingles on treatment. Which brave Pharma company will do this study in the current environment? I suspect a few might take the plunge as vaccine readiness or vaccine responsiveness is now uppermost in the minds of MS experts and their patients. The latter is being driven by the COVID-19 vaccine studies and the demonstration that people on antiCD20 therapies and fingolimod of blunted antibody responses to the vaccines. 

So in summary vaccines, vaccine readiness and derisking infectious complications, in particular herpes zoster, will be the next marketing battleground in the MS DMT wars. Did your HCP discuss the zoster risk with you prior to start you on a DMT?

Anagnostouli et al. Aggressive Herpes Zoster in Young Patients With Multiple Sclerosis Under Dimethyl Fumarate: Significance of CD8 + and Natural Killer Cells. Neurol Neuroimmunol Neuroinflamm. 2021 May 28;8(4):e1017. 

Conflicts of Interest

Preventive Neurology




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

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • How much money would you need in order to be able to start a medium size phase 2 trial of an antiviral ? ( For example the famciclovir trial was about 130 000 pounds if i remember correctly ).

  • Interesting read and analysis, thanks for posting this. I had low total lymphocytes with low CD8 persisting a year after dmf. Still have today for all I know.

    Agree, trial with Shingrix alongside MS treatment (whichever Pharma interested!) could be worthwhile.

    Shingrix private only in UK at present? Might investigate…

    Loving the colour coded posts, but weather too sunny to feel blue today! 🙂

  • When you give alemtuzumab, pwMS are co-prescribed Aciclovir (or similar). Maybe co-prescribe Famciclovir (due to better pharmacokinetics) with DMF? Another way to look at this is, people whose immune systems struggle with HHV3 (VZV) also struggle with HHV4 (EBV, the cause of MS), hence MS develops. I wonder if anybody has looked at shingles incidence in pwMS who don’t take DMF? Oh yes, over 20 years ago Ross et al found the relationship between MS and VZV. Ross RT, Cheang M, Landry G, Klassen L, Doerksen K. Herpes zoster and multiple sclerosis. Can J Neurol Sci. 1999 Feb;26(1):29-32. This would confound a cohort study and I’m not convinced these 2 case reports really add to current knowledge base. Bring on Gavin’s suggestion of high dose anti-CD20 or IRT followed by antivirals.

  • No, HCP didn’t discuss shingles risk. In fact I was just given a list of meds to chose from, over the phone, (this was pre – covid) and left to do my own research and ask any questions I had.

    • that is terrible, but quite common it seems.
      I was directed to the MS Decisions tool on the MS website and told make your choice.
      It’s disgusting isn’t it? The same day as diagnosis, no wonder people get PTSD at the time of diagnosis.
      My neuro didn’t say anything about Zoster either.
      Had shingles as a kid (2nd year junior, so about 9)

  • My ms symptoms started the year following severe shingles which lasted 6 months. Have always felt that this was the trigger. No DMTs, ever. I did read of a study in Thailand that made a connection.

    • Can you post the study here? I had a similar situation and I’m curious to read more about this connection. Thanks

      • Ms linked to shingles: Reuters report from Journal of Infectious Diseases, published June 2011. Could be Chinese Whispers. (Doesn’t feel that way).

  • What about a shingles vaccine for anyone about to start on DMF, or other immunosuppressive therapies. I paid to get mine done along with pneumococcal and Hep B. But should be available to everyone at no cost.

  • So do people with MS on no meds have the shingles jab?
    No clarity at all from hopelessly on the fence MS nurse

  • So if you are on DMF and have already had shingles (years before diagnosis) are you still at risk of a second bout as immune system now not as effective or will you still be able to mount an adequate response, or is it completely unknown?

  • No info on shingles at start of DMT. But I get tested every 6 months for IgG that are still positive 28 years after I had it.
    The grey line in your chart is the incidence in pwMS under treatment or in untreated people? If it is in the untreated then it would indicate that MS lower immune system capacity to respond to virus. Before starting ocrelizumab my CD8 where close to 200 now they are at 140… it may look like MS lowers CD8 immune cells

  • Since Herpes zoster resides in neurons and becomes activated to produce shingles is it the lack of lymphocyte surveillance in the CNS that is causing an increased incidence similar to PML and JC virus? I say this because patients on Natalizumab should not have lymphopaenia.

  • I had shingles the month before the (presumed) onset of MS. As the years went on, I did not have them on DMF or various other MS meds, though I later had them twice on rituximab. I was only advised of shingles risk with alemtuzumab, which was the drug I took after rituximab, and a month or so after discontinuing antivirals as routinely advised, I had shingles again. I went back on antivirals until my lymphocyte count hit normal ranges, and then paid out of pocket for Shingrix at my immunologist’s urging, as in the US I am too young for insurance to cover it, even with four documented cases of it prior.

  • Very interesting meta-analysis on the rate of zoster reactivation on current MS DMTs! Has it been already published? If yes, could you please share the link to the original article?

  • Thanks for sharing this.
    I believe the risk of reactivation of herpes-viral infections with (chronic) lymphopaenic DMF-use is very poorly understood, and underestimated.
    I used DMF for 5 years, with low ALC for 5 years. There was no monitoring of subsets of T-cells (but then again, there’s plenty of research that demonstrates that with DMF, low ALC correlates with especially low CD8 T cells). I had two reactivations of EBV during that time. Second one had lasting effects for more than a year (hence I lost my job).
    I did some research on EBV (and reactivation/new primo-infection with immunosuppression), and impact of chronic low ALC under DMF (and theoretical impact on CD8 T cells). For me, it became clear that there is indeed a theoretical possiblity that my EBV-reactivations were linked to DMF-use.
    But it’s the area of ‘evidence-based’ medicine, so there will have to be a lot more similar cases before that possibility is taken seriously.
    Anyhow, I believe the zoster case is just a tip of the ice-berg for chronic low ALC under DMF (and low CD8+ T cells)…

  • similar findings as regards to PML with DMF:
    -either low ALC
    -or relatively normal ALC, but with pronounced low CD8+ T cells

By Prof G



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