Tag: COVID19

Twitter is where all #MSCOVID19 action is happening

In my inbox this morning there were several emails from people with MS asking the same questions. What should I do; self-isolate or continue as is? Should I stop my DMT or continue it? Am I at increased risk of COVID-19 or not? If I get COVID-19 am I at risk of developing serious disease? Should I purchase a ventilator? I have symptoms of COVID-19 what should I do? Are there any patients with MS who have or have had COVID-19?

I am now creating a template email response directing them to my COVID-19 & MS microsite and saying if after reading the contents this doesn’t answer your question please ask your question(s) using the online portal so that when I make an attempt to answer it everyone else can learn from it.

Twitter is turning orange; MS orange!

There appears to be an increasing number of patients with MS who have or have had COVID-19 that are being reported on Twitter. The following are some of the relevant tweets. If you know of any other cases please let us know.

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CoI: multiple

Yin-yang – day 2 COVID-19 lockdown

The yin and yang of COVID-19.

I have spent day 2 of London’s lockdown doing MS-related webinars; i.e. attending meetings virtually. For every negative, there is a positive, the yin-and-yang of COVID-19.

Environmental activists are claiming SARS-CoV2/COVID19 is simply nature’s way of fighting back. We have pushed planet earth and its environment to the brink and it is responding as predicted.

The fact that academics such as me are working differently has to be a good thing. Do you agree? This is something I am very aware of and is one of the reasons why we started triMS-online; virtual conferences are clearly the way we are going to exchange information in the future. Our MS Academy webinar on “Managing MS remotely during the COVID-19 pandemic” takes things one step further, i.e. how can we revolutionise the management of MS and do as much as possible remotely.

COVID-19 massively reduces air pollution

The combined value of the world’s stock markets is related to global GDP, which in turn represents global consumption. The fact that the major stock markets have crashed by over 30% the world’s global consumption energy and other resources will be plummeting. This is forcing us to work differently. Is this not a good thing?

We may all be anxious and worried about the crisis we are in at present, but it will pass. This virus (SARS-CoV2) is virulent, but not that virulent. A global pandemic of SARS and MERS, with the same level of infectivity as SARS-CoV2, would have been an order of magnitude worse. Maybe we should be saying this pandemic could have been much worse.

I think we will look at back 2019 and 2020 as being the turning point when the world realised we need to take the environment seriously. The images of Australia burning and COVID-19 sweeping across the world is telling us that we are going to have to do things differently in the future.

COVID-19 is forcing us to work differently, which happens to be more environmentally-friendly, and is challenging the Victorian model of healthcare. One very positive thing that may come out of this epidemic is that we may just prevent ourselves from going beyond the environmental tipping point.

Despite my environmental optimism, this does not help you in the here and now, which is why I have spent the better part of the last 3 days getting my MS-Selfie (www.ms-selfie.org) website off the ground and answering your questions about COVID-19. I have addressed the next batch of questions, but as I answer questions more come in so apologies if I haven’t got to your questions yes. Once I am redeployed, which I expect to happen in about a week’s time, I may not have time to do any online activities.

CoI: multiple

COVID-19 Microsite and Q&A

Just to let you know the COVID-19 & MS microsite (MS-Selfie) is now live. I also started to respond to questions via the Q&A page. Hopefully, by curating information in one place, it will stop the repetition of questions and allow pwMS to learn from each other.

I have a backlog of over 50 questions to plough through but will try to get them done over the next few days.

#COVIDMS Managing MS remotely during the COVID-19 pandemic

We had to postpone one of our MS Academy foundation courses this week due to the COVID-19 pandemic. In its place, we are doing a series of webinars. The first one was held yesterday morning with an overview of COVID-19 and how it is forcing us to be creative in managing MS over the next few weeks and months.

The following is my presentation and you can download the slides from my DIY-SlideShare site. I am aware that the MS Academy will be uploading the webinar to YouTube in the next few weeks.

I also spent yesterday designing and populating a #MSCOVID19 microsite written and a beta version is live. It is a work in progress, but over the next few days and weeks, it will become more comprehensive. I will be answering questions and presenting cases studies on the site. I have already had 20+ questions posted via the site and will work on getting these answered an online today.

CoI: multiple

#COVIDMS COVID-19 Q&A

I am getting a continuous stream of questions about MS and COVID-19 infection. The following is an example of the kind of questions that are being asked.

  • Does MS increase my chance of getting COVID-19 infection?
  • Does MS increase my chance of getting severe COVID-19 infection?
  • Does COVID-19 cause MS to relapse?
  • Should I self-isolate because I have MS?
  • Should I stop my DMT if I become infected with COVID-19? 
  • Can you recommend a good source of information to keep me updated on COVID-19 infection and MS?
  • Should I avoid attending my hospital appointments?
  • What about my blood/urine monitoring; should I suspend monitoring during the epidemic?
  • Are there any people with MS who have had COVID-19 infection?
  • What is a safe lymphocyte count?
  • Am I at increased risk because I am on DMT x, y or z?

We are providing answers piecemeal and I get a sense we need to collate them somewhere.

Do you think we should collate these questions into a separate COVID-19 microsite, blog post or blog page? What is the most accessible and searchable format for people with MS? I am aware that a blog creates problems.

Post-script – 18 March 2020

In response to the demand, I am in the process of creating additional pages to our microsite MS-SELFIE, which refers to MS self-management. The Q&A will be in the form of typical questions and anonymised real-life case scenarios. I think the latter is very important in illustrating the subtleties and complexities of clinical practice.

CoI: multiple

#COVIDMS COVID-19 and Ondine’s curse

As a non-virologist, I have been relying on basic principles to make recommendations, and predictions, about what may happen to someone with MS who is infected with COVID-19. However, over time an observational evidence-base will emerge that will either confirm or refute some of these predictions. 

One thing I would not have predicted is Twitter being the platform for some of the early reports. Four patients with MS two on ocrelizumab, one on oral cladribine and other post alemtuzumab have acquired the infection and are apparently doing well. This is good news and congruent with expectations based on the mode of action of these DMTs. Both ocrelizumab and oral cladribine are predominantly anti-B cell therapies and only have a small impact on the T-cell compartment, which is the immunological compartment that is critical for fighting viruses. Anti-viral immunity post-alemtuzumab appears to be normal post immune reconstitution.

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It will be interesting to know what the antibody responses to COVID-19 will be in these patients. A serological or antibody test is urgently needed; this will allow us to test whether or not people have been exposed to the virus. I predict that despite these patients being in anti-B cell therapies they will have detectable anti-COVID-19 antibodies. The reason I say this is that both these agents are unlikely to block antibody responses completely; we already know this for ocrelizumab and as cladribine only depletes B-cells by about 90% it is likely to be similar. The immune system is remarkably resilient and there are deep tissue compartments that are relatively protected from ocrelizumab and cladribine. The latter is supported by data from phase 3 and extension trials and now real-life data, which show that severe viral infections are not a major problem in patients ocrelizumab or cladribine.  

An anti-COVID-19 serology test will allow seroepidemiology studies to be performed, which will allow us to determine how many people have had asymptomatic or undiagnosed mild COVID-19 disease. Variants of this assay will also be fundamental to testing a vaccine.  We will need to know which anti-COVID-19 antibodies are neutralizing, i.e. capable of preventing infection, and which are not. The effective vaccine will probably only have two or three COVID-19 components (antigens or antigen-epitopes) and hence the presence of these epitope-specific antibodies and the absence of antibodies against other COVID-19 antigens will be able to differentiate between vaccine immunity and wild-type infection. 

The following is a list of hypotheses or questions that will need to be answered once we have the tools at hand. 

  1. What is the asymptomatic infection rate in people with multiple sclerosis?
  2. Which DMTs prevent COVID-19 seroconversion after vaccination? I suspect none of the DMTs will suppress seroconversion completely, but based on other vaccine studies ocrelizumab and fingolimod and other S1P modulators will blunt the response. 
  3. Do people with MS on DMTs who are infected become superspreaders, i.e. continue to shed the virus in large amounts for longer periods of time? I predict that natalizumab will be the most likely DMT to do this. This is because it reduces lymphocyte trafficking into mucosal sites that may blunt antiviral responses, which will allow the virus to continue reproducing and being shed in oral and respiratory tract secretions and faeces. 
  4. When an effective antiviral emerges will it reduce or prevent prolonged viral shedding? The corollary to this is the question of whether pwMS on interferon-beta or teriflunomide shed less virus because these classes of DMT are antiviral?  
  5. Are people with MS on DMTs more likely to get severe COVID-19 infection? At the moment we are assuming that immunosuppressed patients will do worse. But this assumption may not necessarily be correct. It appears that severe infection may in fact be due to the immunological response to the virus and that by suppressing the immune response you dampen-down the damage in the lungs. This is why several anti-inflammatory therapies, for example, anti-IL6 and fingolimod, are currently being tested in acute COVID-19 infection. 
  6. How neurotropic is COVID-19 and will MS DMTs, in particular natalizumab, increase the neurotropism of the virus (ability to infect the CNS)? Natalizumab, by partially blocking immune surveillance of the CNS, may create a viral niche that will allow the virus to escape immune detection and cause encephalitis. This is analogous to what happens with PML. This remains my major concern for pwMS on natalizumab. 

In relation to neurotropism, the review paper below is quite sobering; it is extrapolating data on the SARS coronavirus epidemic to COVID-19 and suggests that a lot of the respiratory distress we see from COVID-19 is due to brainstem encephalitis. The hypothesis is that COVID-19 infects small nerves in the lung and other mucosal surfaces. The nerves then transport the virus up their fibres and across synapses into the neurons within the brains of people infected with COVID-19. This so-called retrograde and trans-synaptic transmission of viruses is well described, for example with rabies and other coronaviruses. Once the COVID-19 gets to the brain it destroys nerves cells. In relation to their hypothesis, they suggest the virus damages the respiratory centre in the brainstem that is responsible for the automatic reflex that drives involuntary breathing. If the respiratory centre is damaged you then develop central sleep apnoea; in other words, if you go to sleep you stop breathing and die. This is also referred to as Ondine’s curse or central hypoventilation syndrome. 

In their paper, Li and colleagues describe a survivor: “According to the complaints of a survivor, the medical graduate student (24 years old) from Wuhan University, she must stay awake and breathe consciously and actively during the intensive care. She said that if she fell asleep, she might die because she had lost her natural breath”. This description is typical of central sleep apnoea or Ondine’s curse. 

I think it is too early to accept the central apnoea hypothesis to explain at least part of the COVID-19 respiratory distress syndrome. This will require specific clinical studies on patients in intensive care units to see if they have central sleep apnoea and imaging and post-mortem studies to see if COVID-19 causes brainstem encephalitis. Based on the importance of this hypothesis I suspect intensive care clinicians, neurologists, neuroradiologists, virologists and pathologists are on the case and testing the hypothesis below using several different paradigms. 

If any pwMS have read this paper and are alarmed please don’t be. Like everything in medicine and science, their observations have to be confirmed. At the moment it doesn’t change much except the urgency of the need for an effective anti-COVID-19 antiviral. Ideally, any antiviral will also need to penetrate the CNS, in the event that COVID-19 causes encephalitis. I am also reassured that the one case report of COVID-19 encephalitis reported from China appears to have done well and recovered spontaneously. 

Importantly, this article does not change any of the general advice we are giving to pwMS. Please be vigilant about hand hygiene and avoid high-risk travel and contacts. This epidemic will eventually pass. It is important that we learn as much as possible from the pandemic for the future. 

Li et al. The neuroinvasive potential of SARS‐CoV2 may be at least partially responsible for the respiratory failure of COVID‐19 patients. Journal of Medical Virology Received: 14 February 2020, accepted: 24 February 2020 DOI: 10.1002/jmv.25728 

Following the severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), another highly pathogenic coronavirus named SARS‐CoV‐2 (previously known as 2019‐nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS‐CoV and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID‐19) with clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV. The most characteristic symptom of patients with COVID‐19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse‐connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. In light of the high similarity between SARS‐CoV and SARS‐CoV2, it is quite likely that the potential invasion of SARS‐CoV2 is partially responsible for the acute respiratory failure of patients with COVID‐19. Awareness of this will have important guiding significance for the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.

Acknowledgements: I would like to thank one of our blog readers for bringing this paper to my attention.

Disclaimer: Please note this post, as with all of my blog posts, represents my personal opinions and not the views of my colleagues at Barts-MS.

CoI: multiple

#COVIDMS COVID-19 case study 2

I hope you enjoyed the first COVID-19 case study. The following is another case study that has just arisen in our unit.

Case study: The patient has highly-active DMT having failed a trial of dimethyl fumarate (DMF). She had a brain-stem relapse and her MRI had shown several new lesions. She was switched to oral cladribine and had her first-cycle of 5 days of treatment two weeks ago. She is due for her second cycle of oral cladribine in 2 weeks time. She is very concerned about COVID-19 infection. She works in London and communtes daily to work on the overground.

The COVID-19 ABN guidelines advise us not to do give her her second cycle of oral cladribine.

How are you going to manage this patient?

Postscript – 18 March 2020

Please note I am going to curate these case studies on a dedicated COVID-19 microsite to allow readers to access them in one place.

There is no right or wrong answer her only an opinion and an informed choice. 

This patient has highly-active MS and needs it treated. As she has committed herself to treatment with oral cladribine she will likely be mildly lymphopaenic already from the first cycle of cladribine. 

If we stick to the SIN or ABN guidelines we would have to suspend dosing. However, we may not have given her sufficient cladribine to have an effect on her MS. We do know that one course of cladribine does work and there is published data from Australia that shows this quite convincingly (see MS-Base data below). 

If we don’t complete her course of cladribine could we use an alternate DMT? I would not recommend platform therapies as she has failed on DMF, although teriflunomide may be a holding strategy. Why teriflunomide? It works better second or third-line and has broad antiviral properties that may make it an ideal DMT in this situation. 

Natalizumab would also be an option, but as she does not fulfil the current guidance for being treated with natalizumab under the NHSE DMT treatment algorithm this is not an option at present. Fingolimod will leave her immunosuppressed and starting her on fingolimod when she has a cladribine-induced lymphopaenia is unknown territory and likely to increase her level of immunosuppression. 

My recommendation would be for her to complete her first course of cladribine and to be extra-vigilant about hygiene and social distancing and avoiding high-risk travel. I also want to remind you that the level of immunosuppression after one course of cladribine is relatively moderate. Cladribine only drops T-cell counts by about 40-50% and the levels usually don’t fall into the range that is associated with opportunistic infections. When you analyse the safety profile of those subjects in the CLARITY and CLARITY EXTENSION studies, even those that develop grade 3 or 4 lymphopaenia (lymphocyte counts less than 500/mm3), there really is no obvious viral or severe viral, infection signal apart from herpes zoster. Therefore, I suspect the risk to this patient from severe COVID-19 infection is low. 

Based on the lymphocyte pharmacodynamics and the integrated safety analysis I would classify cladribine as an intermediate risk DMT in relation to severe COVID-19 infection in the same class as ocrelizumab. I really don’t know why it is being put in the same risk category as HSCT and alemtuzumab. 

MS-BASE single course of oral cladribine data

Kalincik et al. Cladribine Versus Fingolimod, Natalizumab and Interferon β for Multiple Sclerosis. Mult Scler, 24 (12), 1617-1626 Oct 2018. 

Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab.

Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed.

Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results.

Conclusion: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon β and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.

Lymphocyte depletion kinetics and impact on subsets post cladribine

Stuve et al. Effects of Cladribine Tablets on Lymphocyte Subsets in Patients With Multiple Sclerosis: An Extended Analysis of Surface Markers. Ther Adv Neurol Disord, 12, 1756286419854986 2019 Jun 18 eCollection 2019

Background: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension). 

Objective: This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5.

Methods: Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48.

Results: Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16+/CD56+ cells (week 5 nadir), a more marked reduction in CD19+ B cells (week 13 nadir), and a less-pronounced effect on CD4+ (week 13 nadir) and CD8+ T cells (week 24 nadir) was shown. There was little effect on neutrophils or monocytes. Lymphocyte recovery began after treatment with CT3.5. Regarding relative proportions of naïve and memory T-cell subtypes in ORACLE-MS, the proportion of naïve-like naturally occurring T-regulatory cells (nTregs) decreased, and the proportion of memory-like nTregs increased, relative to total CD4+ T cells.

Conclusions: CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19+ B cells and relative changes in the proportion of some immune cell subtypes may underlie the clinical effects of CT3.5.

The safety profile of cladribine showing that severe viral infections are not a clinical problem

Cook et al.  Safety of Cladribine Tablets in the Treatment of Patients With Multiple Sclerosis: An Integrated Analysis. Mult Scler Relat Disord, 29, 157-167 Apr 2019.

Background: Treating patients with relapsing multiple sclerosis (MS) with cladribine tablets (two times 4 or 5 days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients for 4 or more years. Safety and tolerability outcomes from individual clinical studies with cladribine tablets have been reported previously.

Objective: Report safety data from an integrated analysis of clinical trials and follow-up in patients with MS to further characterize the safety profile of cladribine tablets.

Methods: Data for patients treated with cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) as monotherapy (n = 923) or placebo (n = 641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral cladribine in patients with MS, and the ONWARD study, in which patients were given cladribine tablets in addition to interferon (IFN)-β or placebo plus IFN-β were included in an All Exposed cohort (cladribine, n = 1926; placebo, n = 802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses.

Results: The incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of cladribine. An increase in TEAE incidence rate was also observed in the cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with cladribine tablets. In general there was no increase in the risk of infections including opportunistic infections with cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia (< 0.5 × 109 cells/L) were associated with an increased frequency of infections, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. Within the constraints of a limited sample size, malignancy rates in the overall clinical program for cladribine in MS did not show evidence of an increase compared to placebo-treated patients and there was no increase in the incidence of malignancies over time in cladribine-treated patients.

Conclusion: The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for infections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently observed TEAEs that occurred at a higher incidence with cladribine relative to placebo. There was also no increase in malignancy rates for cladribine relative to placebo.

Disclaimer: Please note this post, as with all of my blog posts, represents my personal opinions and not the views of my colleagues at Barts-MS.

CoI: multiple

#COVIDMS COVID-19 relevant case study

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

#COVIDMS Lessons from dengue fever for the COVID-19 epidemic

The immune system is a remarkable thing. It has mainly evolved to protect us from infections and has multiple intricate systems to detect and respond to novel infections. I used to warn my patients on the anti-trafficking DMTs, fingolimod and natalizumab, they should be hypervigilant of acquiring exotic new infections, particularly, neurotropic viruses. The theory was that if the virus got to the central nervous system (CNS), whilst you were being treated with one of these therapies, you would be at risk of developing a slowly progressive, untreatable, encephalitis. 

Interestingly, I often used dengue fever as an example. Why? Dengue is an arborvirus (transmitted by mosquito bite) with no effective vaccine. Although it causes a self-limiting infection in most people it is neurotropic and hence can cause encephalitis. It is a very interesting virus in that it is a good example of what can go wrong when the immune system commits ‘original antigenic sin’. There are different subtypes of dengue virus. If you are infected with one subtype and develop antibodies to first subtype these antibodies (original antigenic sin) prevent an adequate immune response to subsequent infection with a different subtype of the virus. This results in subsequent dengue virus infection being more severe with high mortality (2-5%). In short, you don’t want to get dengue fever because of this issue.

In my lectures on derisking DMTs, I used to tell people that I advised my patients on fingolimod and natalizumab against travelling to countries where dengue fever was endemic. If they wanted to visit these countries it was preferable to go at a time of the year when infection risk was low and they should make sure they didn’t get bitten by mosquitoes (clothing, insect repellants, mosquito nets, indoor eating, etc.). Was this wise advice? At the time my advice it was based on a scientific principle and my desire to keep my patients safe. However, when data came along and I had to change my position on this; I now don’t use dengue fever as an example.

The small case series of 15 people with MS, on either fingolimod or natalizumab, clearly show that their immune systems were fine at dealing with dengue fever. All the patients recovered and none of them developed encephalitis. The moral of this story is that data trumps opinions and we should always be prepared to change our position on things. I now use this as an example of that fingolimod and natalizumab are not that immunosuppressive and that it should be fine if you get exposed to a novel infection.

For those people with MS on fingolimod and natalizumab, the dengue fever case study should help reassure you that your immune systems are not that compromised when it comes to responding and clearing a novel viral infection. This is one of the reasons why we are not recommending that our patients on natalizumab and fingolimod stop their therapy in response to the COVID-19 epidemic. 

Fragoso et al.  Dengue Fever in Patients With Multiple Sclerosis Taking Fingolimod or Natalizumab. Mult Scler Relat Disord, 6, 64-5 Mar 2016. 

Dengue fever is the most prevalent mosquito-borne viral illness in humans. There may be different clinical manifestations of the disease, from mild symptoms to hemorrhagic forms of dengue fever and even neurological complications of this viral infection. Blood cells are usually affected, and thrombocytopenia is the hallmark of the disease. This paper presents 15 cases of dengue fever in patients with multiple sclerosis (MS) taking fingolimod or natalizumab. There were no complications of dengue fever or worse outcomes of MS in these patients, and only four of them needed short-term treatment withdrawal due to lymphopenia.

CoI: multiple

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