#COVIDMS COVID-19 relevant case study

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The following is a modified and anonymised email I received from a very concerned patient with MS. His treatment plan has been changed because of the COVID-19 epidemic. How would you advise him?

Dear Prof Giovannoni

I am a 51-year-old lady with active RRMS. I have only had MS for 3 years. 

I am due to have my first ocrelizumab infusion in 2 weeks time. 
My MS is active; I had a new lesion on my last MRI and my disability is progressing rapidly. My EDSS has moved from 2.5 to 3.5 in the last year. I was on glatiramer acetate, which I stopped a week ago. 

My MS team have advised me to delay ocrelizumab treatment indefinitely and to start dimethyl fumarate next week.
My job involves dealing with many members of the public in a very busy retail environment.

Could you advise me if it is okay to start ocrelizumab if my MS team are willing to provide treatment and whether I should self-isolate after treatment because of the amount of contact I have with the public? 

I realise that the Coronavirus situation is a very fast-moving situation, but as I am now only a few weeks away from my treatment date, I want to think through and carefully consider what to do. I don’t want to end up not having the most effective treatment for potentially another  6 to 12 months and missing the therapeutic window to slow down the progression of my MS. 
 
Any advice you can give me is greatly appreciated. 

Thank you 

With best wishes

******

This case illustrates the clinical issues the COVID-19 epidemic is raising and is only one example of what we are having to face in the clinic. There are no easy straightforward answers.

Post-script 14-March 2020

The core issue is that this patient appears to want to get on top of their MS disease activity as soon as possible and doesn’t want to take a chance on a lower efficacy option. If this is the case it excludes interferon-beta and teriflunomide as option, which would be the logical choices based on their putative anti-viral effects. 

I would not recommend DMF. Firstly, DMF is less effective as a second-line DMT and it is immunosuppressive with about 15% of treated patients developing a treatment-related lymphopaenia of <800/mm3. As this usually comes on within the first 6-12 months in may not be the best DMT to start with. 

In a normal treatment environment, fingolimod would be an option, but as it is immunosuppressive I would probably steer away from it as a treatment option. In addition, if a COVID-19 vaccine does emerge quite soon and high-risk patients get early access to the vaccine you don’t want to be on fingolimod. Fingolimod has been shown to blunt vaccine responses. 

Based on its impact on T-cells and innate immunity alemtuzumab is a no-no. You could make the same argument about cladribine, which is now enshrined in print in the Italian and ABN COVID-19 DMT guidelines. However, the data does not necessarily support these positions. The level of T -cell depletion post-cladribine is ~50% for CD4+ T-cells and ~40% for the CD8+ T-cells making a much safer IRT than alemtuzumab. The data on infections in patients who received cladribine in the phase 3 CLARITY  trial, including the subgroup who developed grade 3 & 4 lymphopaenia, is very reassuring with no severe viral infection signal. The advantage of cladribine is that with immune reconstitution occurs this patient will be able to receive a COVID-19 vaccine if and when it becomes available. 

For similar reasons to cladribine, ocrelizumab will be relatively safe.  However, once you start ocrelizumab you need to commit to at least 3 or 4 courses to prevent neutralizing anti-ocrelizumab antibodies. As ocrelizumab blunts vaccine responses it is not the ideal DMT thinking ahead to a vaccine. Ocrelizumab blunts vaccines responses.

This leaves natalizumab. Natalizumab is a high efficacy DMT, with a rapid onset of action and can be reversed by plasma exchange if necessary. It also will not exclude vaccination from a component (non-live) COVID-19 vaccine. From a theoretical perspective, natalizumab cannot be assumed to be safe if this patient became infected with COVID19. Natalizumab has been shown to slightly increase your chances of getting an upper respiratory tract infection and may hence increase the chances of a more severe COVID-19 infection. Then there is the theoretical risk that natalizumab may select for neurotropic strains of COVID-19, but I think this is only a theoretical risk at present. I would also predict that natalizumab has a chance of creating potential COVID-19 superspreaders as it blocks trafficking of T-cells into the gut. Even if this patient was JCV+ve I would still potentially go ahead with natalizumab treatment. To reduce the PML risk this patient could be converted to extended interval dosing of natalizumab after 6 months or switched to another DMT in sy 6-12 months. The elephant in the room is NHS England (NHSE); this patient doesn’t appear to fulfil the current criteria for treatment under the NHSE treatment algorithm. This case, however, highlights, why it is important that NHSE relaxes is criteria for using natalizumab to address the unmet need during the COVID-19 epidemic. 

The other aspect is this patient is in contact with the general public that may increase his chances of being exposed to COVID-19, which may be more important than the other factors predicted above. So if this patient can’t reduce their risk of potential exposure to the virus in the hope of hanging on until a vaccine or anti-COVID-19 anti-viral become available then one of the immunomodulatory DMTs will make the most sense. This is why I would favour teriflunomide as the DMT of choice. It is also worth mentioning that when teriflunomide is used 2nd- or 3rd-line it is more effective. Teriflunomide also does not exclude vaccines later on; vaccine responses to component vaccines is maintained on teriflunomide. 

If this patient is unhappy with the logic of going onto teriflunomide, my second choice would be natalizumab,  followed by cladribine or ocrelizumab. 

This case demonstrates the complexities of treating active MS during the COVID-19 epidemic. There are no right or wrong answers. Whatever decision you make there will be compromises. You may have to compromise on efficacy to increase the safety of the patient concerned and to potentially leverage the other attributes of DMTs to justify your treatment decision, for example in the case of teriflunomide that it is broadly antiviral and does not affect vaccine responses.

CoI: multiple

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.

36 comments

  • I would think provide literature about Ocrevus and viral infections , have her understand the risk vs benefit and proceed in her case if she’s willing given her concerns about her active MS and as long as she verbalizes understanding, maybe offer some options like self isolation/ work from home option if possible after the infusion. If not possible, tecfidera is a good option I’d she has not failed it because she may respond well to it and it has less immunosuppressive effects

    • As a fellow MS patient, in her situation I think I’d try to go ahead with treatment but only if I could somehow create a situation where I was away from crowds for a good while. That would probably mean home working and pretty much staying in. But the situation is changing all the time and if it gets as bad here as in some other places I think it would be too much of a risk. The health service would be too stretched for one thing. Maybe she could leave decision until last minute?

  • I was hoping to find a link to Mouse Dr or someone who might review this first. My brother is a post-graduate professional in New York City and received a copy of this email from a business partner, about how to prepare for and fight the corona virus. By a Dr and Professor who describes himself as a “molecular virologists”. I feel for the woman who is the topic of this post. If she were to go ahead with her transfusion, a good plan of precautionary behavior might help. It would help for all of us too. That is the subject of the email. The Professor who wrote it gives his name and permission to circulate it.
    __________________________________________________________
    The author of this coronavirus precautionary measures is James Robb, MD UC
    San Diego.

    Subject: What I am doing for the upcoming COVID-19 (coronavirus) pandemic

    Dear Colleagues,
    As some of you may recall, when I was a professor of
    pathology at the University of California San Diego, I was one of the first
    molecular virologists in the world to work on coronaviruses (the 1970s). I
    was the first to demonstrate the number of genes the virus contained. Since
    then, I have kept up with the coronavirus field and its multiple clinical
    transfers into the human population (e.g., SARS, MERS), from different
    animal sources.

    The current projections for its expansion in the US are only probable, due
    to continued insufficient worldwide data, but it is most likely to be
    widespread in the US by mid to late March and April.

    Here is what I have done and the precautions that I take and will take.
    These are the same precautions I currently use during our influenza seasons,
    except for the mask and gloves.:

    1) NO HANDSHAKING! Use a fist bump, slight bow, elbow bump, etc.

    2) Use ONLY your knuckle to touch light switches. elevator buttons, etc..
    Lift the gasoline dispenser with a paper towel or use a disposable glove.

    3) Open doors with your closed fist or hip – do not grasp the handle with
    your hand, unless there is no other way to open the door. Especially
    important on bathroom and post office/commercial doors.

    4) Use disinfectant wipes at the stores when they are available, including
    wiping the handle and child seat in grocery carts.

    5) Wash your hands with soap for 10-20 seconds and/or use a greater than 60%
    alcohol-based hand sanitizer whenever you return home from ANY activity that
    involves locations where other people have been.

    6) Keep a bottle of sanitizer available at each of your home’s entrances.
    AND in your car for use after getting gas or touching other contaminated
    objects when you can’t immediately wash your hands.

    7) If possible, cough or sneeze into a disposable tissue and discard. Use
    your elbow only if you have to. The clothing on your elbow will contain
    infectious virus that can be passed on for up to a week or more!

    What I have stocked in preparation for the pandemic spread to the US:

    1) Latex or nitrile latex disposable gloves for use when going shopping,
    using the gasoline pump, and all other outside activity when you come in
    contact with contaminated areas.

    Note: This virus is spread in large droplets by coughing and sneezing. This
    means that the air will not infect you! BUT all the surfaces where these
    droplets land are infectious for about a week on average – everything that
    is associated with infected people will be contaminated and potentially
    infectious. The virus is on surfaces and you will not be infected unless
    your unprotected face is directly coughed or sneezed upon. This virus only
    has cell receptors for lung cells (it only infects your lungs) The only way
    for the virus to infect you is through your nose or mouth via your hands or
    an infected cough or sneeze onto or into your nose or mouth.

    2) Stock up now with disposable surgical masks and use them to prevent you
    from touching your nose and/or mouth (We touch our nose/mouth 90X/day
    without knowing it!). This is the only way this virus can infect you – it is
    lung-specific. The mask will not prevent the virus in a direct sneeze from
    getting into your nose or mouth – it is only to keep you from touching your
    nose or mouth.

    3) Stock up now with hand sanitizers and latex/nitrile gloves (get the
    appropriate sizes for your family). The hand sanitizers must be
    alcohol-based and greater than 60% alcohol to be effective.

    4) Stock up now with zinc lozenges. These lozenges have been proven to be
    effective in blocking coronavirus (and most other viruses) from multiplying
    in your throat and nasopharynx. Use as directed several times each day when
    you begin to feel ANY “cold-like” symptoms beginning. It is best to lie down
    and let the lozenge dissolve in the back of your throat and nasopharynx.
    Cold-Eeze lozenges is one brand available, but there are other brands
    available.

    I, as many others do, hope that this pandemic will be reasonably contained,
    BUT I personally do not think it will be. Humans have never seen this
    snake-associated virus before and have no internal defense against it.
    Tremendous worldwide efforts are being made to understand the molecular and
    clinical virology of this virus. Unbelievable molecular knowledge about the
    genomics, structure, and virulence of this virus has already been achieved.
    BUT, there will be NO drugs or vaccines available this year to protect us or
    limit the infection within us. Only symptomatic support is available.

    I hope these personal thoughts will be helpful during this potentially
    catastrophic pandemic. You are welcome to share this email. Good luck to all
    of us! Jim

    James Robb, MD FCAP

    • Using knuckle for light switches etc – how is that better? You transfer the virus when you use your fist to close a door then, for example.

      The evidence says that face masks can actually encourage face touching.

      Zinc lozenges… Seriously???

      • I’ve had MS for 30+ years. Cancelled my 3rd Ocrevus infusion tomorrow (Friday the 13th, no less! [comedy]). Effects of 1st two doses will be with me for a while even if I don’t go back on. If I get sick with corona, and especially with this guy’s credentials, you want to tell me not to do a little zinc? I have a 30 year track record of trying multiple treatment suggestions from DMT’s to steroids to diets; I don’t know how the combo I was on worked, but it did. What do they have for corona right now? Anything? I thought I’d share his info, that’s what this blog is all about. If I’m down to my last few breaths, I don’t want to be thinking I should have tried the zinc. It might take a “shotgun” approach, to which afterwords (“God willing”, I wouldn’t be asking which one saved me.

  • To me risk of MS worsening is much more urgent situation. I am on ocrelizumab and have not delayed. Me personally as a fellow patient if she were a friend I’d advise her to still get it but I am not a licensed medical provider and these are unchartered waters. I just know for me the disability risk is real and here. Interested to hear prof g advice to her.

  • Sort of related – to Prof G I was wondering if MS patients need to be concerned with risk of MS relapse if they do get COVID 19? That is the biggest concern with flu and why I am so careful to avoid – it’s not concern over beating the infection, ,it’s the worry about it triggering a true relapse and the result of that.

  • Could a dose of steroids be used to treat the active disease? Is the patient able to handle a steroid treatment? That will take a couple of days. Push back infusion by a week, wear gloves in the store/shop.

    • Most deaths from CoVID-19 seem to occur from pneumonitis and secondary pneumococcal infection. The recommended treatment for CoVID-19 in people with COPD or asthma includes steroids and antibiotics. 23 valent pneumococcal vaccination is advised for patients going on Ocrelizumab on some protocols two months prior to commencing treatment and it’s now in short supply.

  • This lady would need to self isolate for 14 days prior to treatment and an undefined period afterwards. The use of concomitant methylprednisolone and chlorphenamine would appear to increase immunosuppression, with it’s consequent increased risk of CoVID19 infection. Does anybody know why these drugs are given together? I plotted a decay model for ocrelizumab and it lingers for months after the steroid and antihistamine are gone.

  • Carry on with Ocrelizumab.

    Tecfidera left me with chronic lymphopaenia, particularly CD8. Perhaps I’m just unlucky.

    • Thanks for this; we talk of DMF being low risk, but I am referring to being DMF with a normal lymphocyte count when I say it is ‘relatively safe’.

  • Hi, I completed round 2 of Lemtrada on the 18th February. My first bloods and review should have been yesterday the 11th March, however, this was cancelled due to concerns Re: Covid 19.

    After round 1 last year my lymph count was still at zero at my first monthly review. How concerned should I be? I have seen lots of advice telling pwMS to delay treatment of Lemtrada,Mavenclad and Ocreveus be several months or switch to another DMT but no advice for those of us that have just received treatment whilst the covid 19 virus was in its infancy.

  • with how the virus is tracking in Europe she is bound to catch it at some stage. Would you consider Nataluzamab for a short period of time due to its action

  • The advice posted here coming from Italy and the UK is not the same as the advice from the US regarding Ocrevus. The latter says that infection risk for covid-19 would be about the same as someone not on Ocrevus. Don´t know which to believe. At this point the US does not have much credibility in many elements of the pandemic.

  • To the person who sent the mail –

    My daughter has been on rituximab (similar to ocrevus) for over eight years now, starting at age 16
    She does not get infections more often than anyone else (fingers crossed)

    If you go ahead, take the common sense precautions and isolate yourself as far as possible

    • Hi

      I contacted Prof G with the above query. It has taken me a while to respond to your helpful and informative comments for several reasons, namely, I’m trying to get my head around what to do next, I don’t usually use blogs/forums and I’ve had a cold/flu virus for the last few days. This has added to my confusion – have I got Covid? would it be good if I had Covid now and then could start Ocrevus treatment relatively free of risk of getting Covid twice? Will I ever be able to get through on 111 to see if I can be tested???

      My feeling is that I should try Ocrevus if my HCP will go ahead, as it seems like the NHS will be in a worse state in a few months’ time than it is currently, and Covid will likely be around for the next 18 months which is a long time to delay escalating treatment. If I wait to see what my MRI scan results are from my scan due next week I may be waiting for several months and have to decide what to do at the peak of the epidemic.

      I shall look into other available drugs – my gut feeling is to go for a higher efficacy drug. I am encouraged by those of you indicating that Ocrevus does not necessarily make you an infection magnet. I am concerned about the need to self-isolate and distance myself socially as it is not compatible with my job and I wonder how long my employers will be patient with self-isolation. Though this might be the case whether I escalate treatment or not as I suppose I am still in a vulnerable group and won’t want to brave public transport and busy city centre irrespective of type of treatment I proceed with.

      Once again, thank you everyone for all your comments! I feel I am not struggling alone.

    • I deliberately stayed out of the conversation to see how it evolved. I will make a detailed comment as a post-script.

  • I have now added a post-script to the COVID-19 relevant case study to explain my thinking about DMT choice in these troubled times.

    • Thank you. 2 questions:
      “It also will not exclude vaccination from a component COVID-19 vaccine”. First line of vaccination will be live from what I read. Attenuated vaccines will take longer. I thought live vaccines were no go for natalizumabers?

      2. How likely is it that covid+19 infection induces a nasty elapse for a longterm NEDA2/3 natalizumaber? Would plasma exchange follow in that case? What about steroids?

      • Yes, live vaccines are not recommended in natalizumabers, which is why I refer to as being a component (non-live) vaccine. I think the 1st vaccine will likely be a DNA vaccine; much easier to manufacture at scale.

        • Thanks for clarifying. For the sake of saving me hours educating myself on vaccines, are DNA vaccines live or dead?

          And what about that dreaded covid-induced relapse?

      • Re: “How likely is it that covid+19 infection induces a nasty elapse for a longterm NEDA2/3 natalizumaber?”

        Unlikely if you are on the drug. If the person has new neurological symptoms it will important to exclude other causes, in particular, COVID-19 encephalitis.

      • I am not a doctor but I did do first aid, ABC if your airway isn’t open you can’t breath, you die, if you are not breathing you die so you give breath (historically..now no lips) , circulation plug the hole.so do you deal with relapse or worry about something that may not haplen

      • French authorities have warned that widely used over-the-counter anti-inflammatory drugs may worsen the coronavirus.

        The country’s health minister, Olivier Véran, who is a qualified doctor and neurologist, tweeted on Saturday: “The taking of anti-inflammatories [ibuprofen, cortisone … ] could be a factor in aggravating the infection. In case of fever, take paracetamol. If you are already taking anti-inflammatory drugs, ask your doctor’s advice.”

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