Barts-MS rose-tinted-odometer: ★★★★★ COP26 Land Green & Ocean Blue #37328c #8cdc73
Did you know that the world will use between 8 billion and 10 billion syringes for COVID-19 vaccinations alone? Apart from this, the world uses approximately 16 billion syringes per year. Over half of these are used outside of the health care system each year by individuals with diabetes, migraines, allergies, infertility, arthritis, HIV, hepatitis, multiple sclerosis, osteoporosis, psoriasis, or other conditions.
With COP26 top of mind do you ever consider the environmental impact of your DMT? I have simply assumed that because they are medicines and prescribed for a serious disease the environmental impact is justified. Could the environmental impact of injectable or intravenous therapies be another reason to embrace oral treatments? Or is the environmental impact related to the manufacturing process of oral treatments greater?
Is this something that you would consider to be an important factor when making a decision about which DMT to choose? For example, would a lower environmental impact of a 6-monthly ocrelizumab infusion be a factor in choosing it over a monthly subcutaneous injection of ofatumumab? After all, both of these DMTs are anti-CD20. Would you not want to choose the one with the lowest environmental impact?
Some of you may already be aware of our ClinicSpeak DMT decision aid we run to help pwMS make decisions about which DMT to start. Do you think we should include the environmental impact of the various DMTs on the list of factors to consider when making a decision?
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 and are not meant to be interpreted as personal clinical advice.
Barts-MS rose-tinted-odometer: ★★★★★ (seeing grey – it’s a very grey Saturday)
Whenever you bring up the topic of using more effective DMTs or flipping the pyramid you get pushed back because of the potential risks associated with these treatments. One risk is the big-C or secondary cancers. It is therefore very reassuring that an analysis of the FDA adverse event reporting system database revealed no safety signal for increased cancer risk among the approved MS DMTs.
The only potential safety signal that was detected in a so-called sensitivity analysis concerned interferon-beta-1a (Rebif/Avonex/Plegridy) and alemtuzumab.
The message is that the cancer risk associated with MS DMTs is probably quite low and not nearly as high as the risk associated with more potent immunosuppressive therapies and the so-called mutagenic therapies. Please note none of our licensed DMTs is mutagenic. Please note this analysis does not include AHSCT, which typically uses cyclophosphamide to mobilise stem cells and to ablate the immune system. There is clear evidence that people who have had AHSCT are at increased risk of developing a secondary malignancy, which is almost certainly a consequence of exposure to cyclophosphamide and other chemotherapy agents given as part of the procedure.
This analysis also puts the FDA cladribine black box warning into perspective, i.e. the real-life data suggests there is no increased cancer risk with cladribine and supports my interpretation of the data that cladribine is not associated with secondary cancer risk. The apparent cladribine cancer risk in the phase 3 or CLARITY trial was driven by the fact that there were zero cases in the placebo arm, which was the outlier. Let’s hope this data will allow pwMS to put the ‘potential cancer risk’ of DMTs into perspective and give them the confidence to access more effective therapies earlier on in the course of their MS.
It has now become abundantly clear that the earlier the average person with MS is treated with a high efficacy DMT the better their outcome. The message is treat-early and treat-effectively.
Aim: While the efficacy of Disease-Modifying Therapies (DMTs) for patients with Multiple Sclerosis (MS) is established, little is known about their long-term safety. Cancer-risk after DMTs use remains unclear. This study aims to investigate whether the prescription of DMTs for patients with MS increases the risk of reporting cancer.
Methods: Data from the FDA adverse-event reporting system were extracted from 2004 until 2020. After data cleaning, the crude and adjusted Reported Odds Ratios (cROR, aROR) for cancer were calculated for DMTs with Interferon-beta1a as the reference drug. Sensitivity analyses investigated the group of reports with multiple registered DMTs, the effect of indication restriction, and the results when using the rest of the DMTs as reference.
Results: For malignant tumors, aROR (CI 95%) were: Cladribine 0.46 (0.18-0.95) Dimethyl fumarate 0.30(0.27-0.34), Fingolimod 0.61(0.53-0.70), Glatiramer 0.50(0.43-0.58), Alemtuzumab 0.84(0.64-1.08), Interferonbeta-1b 0.49(0.42-0.56), Natalizumab 0.36(0.34-0.39), Ocrelizumab 0.48(0.29-0.74), pegInterferonbeta-1a 0.35(0.26-0.48), Siponimod 0.89(0.47-1.54), Teriflunomide 0.25(0.21-0.30) adjusted to age, gender and concomitant medications. In the sensitivity analysis, when the rest of the drugs were used as a reference, Interferon-beta1a and pegInterferon-beta1a had aROR (CI 95%): 2.60 (2.47-2.74, p<0.001), and Alemtuzumab 1.47 (1.13-1.88, p=0.003).
Conclusions: No safety signal for increased cancer-risk was detected among the approved DMTs, although more robust evidence is needed. A potential safety signal detected in the sensitivity analysis concerning Interferon-beta1a, Alemtuzumab, requires further evaluation with more robust evidence.
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.
Thank you for completing yesterday’s poll. It is quite clear that you, our blog readers, want us to prioritise the following changes to the way we prescribe DMTs in the NHS. The most important priority is for pwMS to access immune reconstitution therapies (alemtuzumab, cladribine and HSCT) early as 1st-line therapies for active MS. Please note if you have rapidly evolving severe MS (RES) you can be treated with alemtuzumab and cladribine first-line, but outside of this very small group of patients, we can’t prescribe IRTs first-line. For more information on RES vs. active MS classification system and its implications for some pwMS, I would recommend you read ‘Watchful Waiting 2‘.
The next priority is access to natalizumab, a very high efficacy therapy, as 1st-line therapy for active MS. At the moment the only agent that covers this broad bracket is ocrelizumab. My reading into this is that if you don’t have RES but just active MS, you would like more choice and not simply have one high-efficacy option first-line.
The third priority relates to treating advanced or progressive MS, i.e. getting rid of the stopping criteria when people with MS reach EDSS 7.0 (wheelchair) and liberalise the prescribing of ocrelizumab and siponimod for primary progressive and secondary progressive MS, respectively. My interpretation of the latter is that you want to challenge the active vs. inactive progressive MS dichotomy.
Finally, treating asymptomatic MS and liberalising the use of platform therapies and fingolimod is not a priority. This worries me because as we move into an area of testing and exploring the induction-maintenance paradigm we need to be able to use platform therapies 2nd- and 3rd-line. I have made the point before that pwMS are not going to be able to remain on anti-CD20 therapies indefinitely because of the potential risks; for example, as your immunoglobulin levels drop and serious infections increase the benefit-risk balance changes. Therefore, we are going to need to test de-escalation approaches to derisk anti-CD20 and other chronic immunosuppressive treatments. This is the rationale of the iTeri study that I have proposed doing; i.e. induction with ocrelizumab or rituximab followed by maintenance with teriflunomide.
I would be interested to know if you are surprised by the poll’s findings?
I wonder if the Australian neurologists chuckle when they read this sort of blog post? They have no restrictions on how they treat MS and can use any DMT, including AHSCT, as they and their patients see fit. If only the NHS would allow us to practice in this way 🙁
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.
Barts-MS rose-tinted-odometer: ★★★★★ (seeing green; the green shoots of spring)
I was asked yesterday if I could have a wish and change three things in relation to the prescribing of MS DMTs in the NHS, which ones would I prioritise? Can you help? The idea is to make changes based on how we would want to manage MS proactively as possible and to give pwMS choice. The idea of this exercise is to get an idea of what is most important to the MS community given our current restrictions. Please note you can add your own priority at the bottom of the survey if you don’t feel satisfied with the limited selection provided.
The poll will take 3 seconds to complete and you are welcome to complete it if you live outside of the UK and/or are not someone with MS.
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.
Did you know that MS disease activity defines if you are eligible for therapy and which therapy?
The following is a list of definitions that are generally applied to MS in England.
Inactive: Patients with MS with no relapses or imaging features of disease activity in the last 2 years.
Active: Patients with active disease are defined as having one or more relapses in the preceding 2 years and/or evidence of one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI in the last two years.
Highly active: Patients with high disease activity despite treatment with a platform DMT. This group is defined as patients who have failed to respond to a full and adequate course of a platform or other DMT. Patients should have had at least one relapse in the previous year while on therapy and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.
Rapidly evolving severe or RES: Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.
Disabling relapse: if the relapse is severe enough to affect the social and/or occupational functioning of the patient.
The problem with these definitions is that they entrench the clinico-radiological worldview of MS and are not based on biology or for that matter data. For example, the RES definition was a negotiation between Biogen representatives and the EMA to get natalizumab licensed in Europe. RES MS was not a prespecified population and there were no requirements for study to subjects to have an increasing lesion load on MRI or to have prior relapses classified as disabling or non-disabling to be included in the AFFIRM study (phase 3 natalizumab study). So in reality the RES population is hypothetical. Despite this, the concept of RES MS has stuck and is likely to be entrenched in our MS algorithms for the foreseeable future, unless we challenge these definitions.
So if you are NEDA-2, i.e. have no relapses or focal MRI activity in the last 2 years, you have inactive MS. The latter definition is independent of disability worsening, accelerated brain volume loss, raised neurofilament levels, worsening cognition, accelerated retinal nerve fibre loss, slowly expanding lesions or progressive spinal cord atrophy. In other words, the definitions are based on clinical relapses and focal MRI activity, which is our concept of active inflammation. None of our current definitions for treatment acknowledges smouldering disease; hopefully, this will change in time.
Clearly, these definitions are subject to change or hacking as technology evolves. So if you move from a 3 tesla to a 7 tesla MRI you may find it easier to show a change in lesion load due to the better definition of lesions and the ability to see cortical lesions. Simply increasing the number of MRI scans will increase the sensitivity of the measure of activity, particularly if you are using Gd-enhanced MRI scans.
The definition that worries me the most is RES. The number of people with RES is getting smaller simply because we tend not to let someone diagnosed with MS after one relapse wait to have a second relapse before treating them. Therefore the number of patients with RES is going down and this is why so few pwMS are eligible for cladribine, alemtuzumab and natalizumab as first-line therapies. The only highly effective therapy that is allowed first-line for active MS is ocrelizumab. So if you want to flip the pyramid and start on one of the other top-tier DMTs you have to either start on ocrelizumab or wait and hope you have a disabling attack within 12 months of your first attack to become eligible for natalizumab or one of the licensed IRTs (alemtuzumab or cladribine).
Waiting and hoping to become RES is what I call watchfully waiting 2.
This watchful waiting for the next disabling attack to become eligible is really incompatible with the concept of time-is-brain and hence access to IRTs are not really a first-line option for the majority of people with recently diagnosed MS.
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.
Many of my colleagues have criticised and reprimanded me for being over-enthusiastic in stating that immunosuppressive MS DMTs are relatively safe for pwMS if they happen to develop COVID-19 whilst on treatment. However, the issue has been asymmetry of knowledge. I have known that patients on DMTs who get COVID-19 are doing well. This is based on knowledge acquired from multiple sources albeit confidentially. I have been trying to encourage my colleagues to put this information into the public domain, but clearly it is not happening soon enough. The delays in getting this information out to you the MS community has been far too slow. Do you agree? The good news is there are now platforms to speed up the dissemination of data; let’s hope it changes behaviour.
At last, the Italian COVID-19 and MS pilot data has been published in a peer-reviewed journal. They report on the first 232 patients with MS who developed COVID-19. I actually commented on this data on the blog on the 10th April and it was only published yesterday. There is nothing new to report. This delay is simply unacceptable as HCPs and pwMS need this type of information to challenge current treatment guidelines with evidence and more importantly, pwMS need this information to make potentially life-threatening decisions about their MS care. The number of patients on each individual DMTs is probably too small to make a definitive judgement, but sufficient to be reassuring.
So if any of my colleagues are reading this post please put your data out in the public domain ASAP and in a form that is accessible to all. There are several platforms for doing this including the weekly iWiMS webinars (see below) and the MSIFs Global Data Sharing Initiative. The latest data presented in the most recent iWiMS webinar is in line with the Italian data and remains very reassuring. It clearly supports the need to update treatment guidelines and develop an exit plan. At the moment I am still on version 4 of my DMT table.
So what are the wider consequences of asymmetric knowledge? To understand this you need to become an economics scholar. Asymmetric knowledge is an economic construct to explain the consequences of what happens where one party has more or better information than the other in a transaction. It creates an imbalance and can sometimes cause market failure, in this case, a potential moral hazard for pwMS and the wider MS community. Other, examples of this problem are adverse selection and monopolies of knowledge. I abhor the latter and it is particularly important that we try and fight it.
In addition to me falling out with several of my colleagues over this issue, many wars have been caused by asymmetric information. If you are interested in reading more about this topic I would recommend Joseph Stiglitz’s work; he won and shared the Nobel prize for economics in 2002 for “analyses of markets with asymmetric information”.
On March 14, 2020, we sent the case report form to more than 200 Italian neurologists from about 90 multiple sclerosis centres across Italy. As of April 7, 2020, we have collected data on 232 patients from 38 centres, 57 of whom tested positive for COVID-19 and 175 of whom had suspected COVID-19 symptoms but did not have a positive test (appendix p 1). Mean follow-up was 12·6 days (SD 7·4). The severity of COVID-19 infection in 232 patients was classified as mild (no pneumonia or mild pneumonia) in 223 (96%), severe (shortness of breath, respiratory rates ≥30 breaths per min, blood oxygen saturation ≤93%, PaO₂:FiO₂ <300 mmHg/%, and an increase in lung infiltrates of >50% within 24–48 h) in four (2%), and critical (respiratory failure, septic shock, and multiple organ dysfunction or failure) in six (3%). Of the six critical patients, one recovered and five died; all had a positive swab (appendix p 2). 21 patients had undergone a 5-day course of methylprednisolone within 3 months before the onset of COVID-19.
So if you are someone with MS who is shielding or being very careful about social distancing and want to avoid getting COVID-19 you may be considering what your own exit strategy is. How do you de-risk yourself and prevent yourself from becoming infected with SARS-CoV-2?
At present, it looks as if the UK government’s strategy is to ring-fence you with people who are immune to SARS-CoV-2, the so-called herd immunity paradigm, and hope an effective vaccine emerges in the next 12-18 months to secure the safety of the high-risk or vulnerable population. This strategy is high-risk because there is no guarantee that sufficient numbers of healthy people in the general population will get COVID-19 to ring-fence the vulnerable. To be honest there are too many vulnerable people. In addition, there will always be holes in the science behind the herd-immunity paradigm; who says immunity to SARS-CoV-2 will be long-term and why wouldn’t new strains of virus emerge to fool the immune system. This means that vulnerable people will have to live in fear that they may acquire COVID-19 unless they get an asymptomatic/mild infection and/or vaccinated and have proof they have neutralising anti-viral protective immunity against SARS-CoV-2.
So the next questions are if and when an effective SARS-CoV-2 vaccine emerges (1) how good will the vaccine be and (2) if I am on a disease-modifying therapy will I respond to the vaccine?
In general, vaccines can be hit and miss. Politicians, particularly Donald Trump, and the general public seem to think that an effective vaccine is imminent. Yes, it may be but it is more likely, based on industry timelines, that an effective vaccine for SARS-CoV-2 is years away. Developing a vaccine for respiratory viruses is not easy, particularly for viruses that mutate rapidly and have mechanisms built into their nucleic acid which results in antigenic drift, i.e. the proteins they express on their surface rapidly mutate to escape immune detection. The latter is a particular problem with for example the influenza virus; antigenic drift happens annually. We also know this is a problem with coronaviruses because immunity is not life long and wanes within years. This is why we get recurrent common colds.
The other problem with viruses and vaccines is the so-called original antigenic sin. This is when you make an immune response to a virus or vaccine antigen. The virus then mutates and when you get infected with the new strain the antibodies you make to the original strain or vaccine don’t neutralise the new strain and may even enhance infection with the new strain. In addition, your immune system doesn’t treat the new strain as a new infection and thinks it is the original strain and hence doesn’t make new antibodies against the new strain. This why it is referred to as antigenic sin. Vaccine development has a long history of failing because of these sorts of issues and is why we haven’t got highly effective vaccines against major viruses such as dengue fever.
Another issue with SARS-CoV-2 is that it looks like some of the important binding sites on the spike protein of the virus are heavily modified with sugar molecules. This means that neutralizing antibodies against SARS-CoV-2 may need to be against so-called glycoprotein segments of the spike protein. Glycoprotein vaccines are much more difficult to make and in themselves are less effective in inducing antibodies than pure protein vaccines. The reason for this is that the immune system processes sugar (glyco) antigens differently to protein antigens.
I am telling you all this to make you aware that vaccine development is difficult, very difficult, and there are a lot of issues that will need to be considered to make sure a vaccine against SARS-CoV-2 is effective and safe.
The other issue is having an immune system that is capable of mounting an immune response to a vaccine. I think in general a live-attenuated SARS-CoV-2 vaccine is unlikely to be developed. Live vaccines tend to be legacy vaccines from an era before we had the tools to make recombinant proteins. Therefore it is highly likely that all the vaccines that will be developed will either be nucleic acid, protein or glycoprotein component vaccines. In general immune responses to vaccines are blunted by immunosuppressive therapies. This has relevance to pwMS because the DMT you are on may block the required immune response to the vaccine. So your careful and patient waiting for an effective vaccine may be futile.
In general, interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate and natalizumab are unlikely to block or attenuate immune responses to a component SARS-CoV-2 vaccine. Similarly, once immune system reconstitution has occurred post alemtuzumab, cladribine, mitoxantrone or HSCT vaccine responses should be restored to normal or near normal. In the depletion phase of IRTs (immune reconstitution therapies) it is likely that vaccine responses will be blunted. In the case of S1P modulators, such as fingolimod and siponimod, and the anti-CD20 therapies (ocrelizumab and rituximab), which are continuous immunosuppressive therapies, vaccine responses are likely to be blunted. I use the term blunted rather than inhibited responses because pwMS on these therapies may still make antibodies to the vaccine components but not to the required level to create protective immunity.
The story with anti-CD20 therapies is potentially more complex. Surprisingly, antibody response to common vaccines occur on anti-CD20 therapies, but antibody response to glycoprotein vaccines, for example, the pneumococcal vaccine are blunted or inhibited the most. This may be particularly relevant to a SARS-CoV-2 vaccine that is likely to require antibodies to glycoprotein antigens to generate neutralizing antibodies, i.e. antibodies that neutralise the virus and prevent infection.
Is this information important for pwMS? Yes, I think it is and may affect whether or not pwMS start or continue treatment with S1P modulators or anti-CD20 therapies. In other words, if you want to make yourself ‘vaccine ready’ you need to consider your DMT choice.
As a research group, we are very interested in the antibody responses to SARS-CoV-2 in pwMS who have had COVID-19. We are in the process of trying to rapidly develop an antibody assay for IgG and IgM antibodies that can differentiate between binding and neutralizing anti-SARS-CoV-2 antibodies. This will allow us to study whether or not the immune response to SARS-CoV-2 is different in patients on S1P-modulators and anti-CD20 therapies and to compare these responses to patients on other DMTs and to patients who are not on DMTs. This will potentially allow us to give patients detailed information in the future about their risk of getting delayed COVID-19 and whether or not they respond to emerging vaccines once they arrive.
In conclusion, as we start to think about exit strategies for pwMS post-COVID-19 being able to respond to a future SARS-CoV-2 vaccine is a major factor HCPs and pwMS need to consider when deciding on what DMT to start or continue with for the long-term.
Now some questions for you. For those of you who consider yourself, ‘COVID-19 vulnerable’ is being able to respond to a future SARS-CoV-2 vaccine relevant to you? Does it affect your thinking about which DMT you want to be treated with? Please let’s start a discussion on this important topic.
I think the vaccine issues is important enough for me to have added a new column to my DMT COVID-19 table (version 4.0) and to change the colouring scheme to a patchwork.
This week saw several bits of information appear that has led me to change my position on several DMTs in terms of their risk for pwMS during the COVID-19 pandemic.
Firstly, the verbal update by Maria Pia-Sormani on the Italian cohort of patients with MS who had COVID-19. These figures were given during the iWiMS weekly COVID-19 &MS webinar. There are now 380 cases of pwMS and COVID-19 reported in the Italian register with only 5 deaths. The mortality rates are well below that of the general population and suggest that pwMS are not at increased risk of severe COVID-19. This is good news. This data also supports the hypothesis that mild-to-moderate immunosuppression may be good and in fact, reduce the chances of pwMS getting severe COVID-19. This is not surprising as severe COVID-19 is almost certainly immune-mediated disorder. The five patients that died (see table below) tended to be older, have more advanced disease and comorbidities.
It is now clear that SARS-CoV-2 is neurotropic with the second, but first published, case of meningoencephalitis with virus detectable in the spinal fluid. This now increases the risk of natalizumab for pwMS. You don’t want to be on natalizumab if SARS-CoV-2 disseminates to the CNS. It is very important that if you are on natalizumab and get COVID-19 that you look-out for CNS symptoms. The fact that most MS centres have shifted their patients onto EID (extended interval dosing) will reduce this risk but it remains concerning. For more information on how EID reduces this risk please see my explanation on MS-Selfie.
At a personal level I have now 6 patients with MS on various DMTs who have all come through having had COVID-19 without any problems. I have asked them to register themselves on the MS register study and I will be reporting them next week.
I would urge you to watch the weekly iWiMS webinar which will keep the MS community up-to-date with what is happening in relation to COVID-19 and MS.
I therefore updated my table and have added a ranking to reflect the changing advice. Please note I have downgraded the risk associated with anti-CD20 therapies based on the emerging evidence as well. More on this later.
Novel coronavirus (SARS-Coronavirus-2:SARS-CoV-2) which emerged in Wuhan, China, has spread to multiple countries rapidly. We report the first case of meningitis associated with SARS-CoV-2 who was brought in by ambulance due to a convulsion accompanied by unconsciousness. He had never been to any foreign countries. He felt generalized fatigue and fever (day 1). He saw doctors nearby twice (day2 and 5) and was prescribed Laninamivir and antipyretic agents, His family visited his home and found that he was unconsciousness and lying on the floor in his vomit. He was immediately transported to this hospital by ambulance (day 9). Under emergency transport, he had transient generalized seizures that lasted about a minute. He had obvious neck stiffness. The specific SARS-CoV-2 RNA was not detected in the nasopharyngeal swab but was detected in a CSF. Anti- HSV 1 and varicella-zoster IgM antibodies were not detected in serum samples. A brain MRI showed hyperintensity along the wall of right lateral ventricle and hyperintense signal changes in the right mesial temporal lobe and hippocampus, suggesting the possibility of SARS-CoV-2 meningitis. This case warns the physicians of patients who have CNS symptoms.
Yesterday I had the experience of a patient with highly active MS pull out of being treated with ocrelizumab (Ocrevus) because of concerns around being infected with the coronavirus COVID19. I suspect this will be the first of many patients with multiple sclerosis to do so.
It is clear that COVID19 epidemic is now a pandemic, i.e. it has involved enough continents and countries to be considered a major and very serious global health emergency. This was predicted to happen many weeks ago. Several basic epidemiological factors indicated that this would occur:
A long asymptomatic period during which infected people shed the virus and are infectious
Asymptomatic shedders who don’t get ill
An estimated R0 (r-zero) of 3-5, which is an estimate of how many people or contacts that an infected person infects
The identification of superspreaders; individuals who seem to be able to infect a large number of people
Excessive national and international travel; the initial epidemic in Wuhan happened to coincide with the largest annual human migration of people (see graph below). Approximately 400 million people migrate in relation to the Chinese New Year and a lot of that migration was international, which explains why the virus has spread so rapidly to other countries
Ubiquitous air travel, involving large airports and hubs, which has the ability to spread viruses very rapidly to people on the same aircraft and then to disperse them to all corners of the world before they get symptomatic disease
COVID19 is also a new human pathogen having jumped to humans from animals and as a result of this, we have no pre-existing herd immunity that could buffer or reduce its rate of spread.
At the moment the mortality or death rate form the virus is approximately 2%, or 1 in 50, with the majority of deaths affecting the elderly or infirm. The mortality is likely to fall as case ascertainment and reporting gets better. This occurs because the less ill get counted into the so-called denominator. At a population level, this death rate has major implications for healthcare systems. The majority of the deaths are due to pneumonia and these sicker patients require intensive care support. All countries simply don’t have enough ITU beds to support large numbers of ventilated patients. In fact, Britain has too few ITU beds already, without having to deal with the coronavirus pandemic.
What to look out for?
Coronavirus infection presents very non-specifically with flu-like symptoms, i.e. fever, a cough, or difficulty breathing. Most cases are mild. Those who have died in often have pre-existing health conditions and this is where the problem lies for pwMS. If you have advanced MS, a history of recurrent chest infections and/or you are on immunosuppressive therapies you are considered at high risk of complications from coronavirus infection. The latter risk extends to other infections as well, which is why, for example, it is our policy to recommend the annual flu vaccine to all of our patients with MS.
What to do?
If you have symptoms following travel to a high-risk area or after coming into contact with someone who has had coronavirus infection you should contact the NHS hotline so that appropriate samples can be submitted to Public Health England for testing. In addition, you will need to self-isolate or be treated in isolation.
I would not recommend stopping your disease-modifying therapy. The immunosuppression associated with MS DMTs is relatively mild-moderate and hence most pwMS can handle infections relatively well. The exception being alemtuzumab (Lemtrada), and possibly cladribine (Mavenclad), during the lymphocyte depletion phase. Cladribine is less of a problem as T-cells are on average depleted by ~50%, whereas with alemtuzumab the T- and B-cell depletion is typically greater than 90%. The good thing about IRTs (immune reconstitution therapies) is that once your immune systems have reconstituted they are competent to deal with infections.
Although fingolimod (Gilenya) causes lymphopaenia it is not an absolute lymphopaenia as lymphocytes are sequestered or trapped in lymph nodes. Therefore, pwMS on fingolimod can in general deal with viral infections, although they have more frequent and possibly more severe infections. This also applies to other S1P modulators (siponimod, ponesimod, ozanimod, etc.), in other words it is a class effect.
Viral response on anti-CD20 therapies (rituximab, ocrelizumab and ofatumumab) should also be maintained, but maybe blunted as B-cell and antibody responses may be necessary to help clear the virus. The infections that people on anti-CD20 therapies have a problem with are encapsulated bacteria (pneumococcus, meningococcus, Haemophilus, etc.).
Coronaviruses can rarely cause and encephalitis, typically in severely immunocompromised patients. This would indicate that as a class coronaviruses are neurotropic. I am not aware of any data on whether or not COVID19 causes encephalitis. If COVID19 is neurotropic encephalitis would be a risk for people on natalizumab (Tysabri). As natalizumab blocks immune surveillance of the CNS, a person on natalizumab who develops a COVID19 encephalitis would be in danger of succumbing to the infection. The latter is analogous to PML, which is also viral encephalitis.
DMF (Tecfidera) is only mildly immunosuppressive and in my opinion, is unlikely to be a major worry in the event of you acquiring a COVID19 infection. The one caveat being patients on DMF with a significant lymphopaenia, i.e. with a total lymphocyte count of less than 0.8 x 109/L or 800/mm3.
Teriflunomide (Aubagio), glatiramer acetate (Copaxone) and interferon beta (Betaferon, Avonex, Rebif, Plegridy) are not immunosuppressive agents and hence should not increase your chances of having a severe COVID19 infection.
Whilst the risk of COVID19 infection to the general public, and hence pwMS, is very low I would not recommend changing your DMT or avoiding starting any planned infusions. I would, however, recommend that if you are immunosuppressive to be extra-vigilant about hygiene (handwashing, etc.) and to avoid travelling to high-risk areas. If you are travelling through high-risk areas, for example, China, Hong Kong or Singapore you need to be more vigilant.
I am also getting asked for advice about face masks. The evidence that cheap surgical masks work for coronaviruses is limited. Coronaviruses are spread in a different way to the flu virus. Coronaviruses are not aerosolized in the same way as the flu virus and hence are not breathed in, but are rather spread by droplets. These stick to surfaces and hence the need to wash your hands. So masks are likely to work both ways for coronavirus, where they are not very effective for flu. One thing masks do is they make you wearer change your behaviour in other ways.
If you are travelling to a high-risk area and are going to use a face mask can I suggest using a good quality one, i.e. an FFP3 mask that filters out small particulate matter? These work for larger organisms such as TB and may help reduce transmission of COVID19. It is important that you have the masks fitted and you know how to use them properly. Within the NHS the latter is typically done by a healthcare professional with the necessary training on how to assess adequate mask fitting and usage.
As we are not infectious disease experts or virologists I would recommend following the NHS’ and Public Health England’s website for up to date advice.
What did I recommend for my patient above?
As there was no way he was going to be treated with ocrelizumab I ended-up recommending teriflunomide. The advantage of teriflunomide is that it is not immunosuppressive and has pan anti-viral activity against many viruses.
Clearly the advice given above applies to pwMS living in the UK. In COVID19 hotspots, e.g. China, it may be safer to delay treatment with immunosuppressive therapies until the epidemic has passed and there is herd immunity to protect you. In addition, a COVID19 vaccine may become available within the next 6-12 months. Therefore, it may be worthwhile initially choosing an immunomodulatory DMT that won’t interfere with future vaccine responses.
P.S. (27-Feb-2020): Please be aware that the advice above may be time-limited. Once the coronavirus becomes established in the community and person-to-person spread becomes more common and the source of infection can’t be traced, which is happening in China and Italy at the moment, then the public health advice may change. In this situation reverse quarantine may be necessary, i.e. to ask high-risk individuals to self-isolate themselves so as not expose themselves to the virus. At the moment this is not necessary in the UK as all the cases have been linked to a clearly identifiable source.
Using fiction to teach and learn about MS is what I am turning to more and more. An old-fashion case scenario is a powerful tool for illustrating the difficulties we have in clinical neurology. We can create a clinical problem that is not necessarily answered by trial data or reading the summary of product characteristics. This is where clinical acumen and reasoning by analogy are required to help make a decision relevant to that individual patient. The following is an example of a case I recently used. It was quite interesting that in a room of about 10 neurologists there was no obvious consensus to the questions posed by the case scenario.
Medical fiction – case scenario malignancy
A 47-year woman with active relapsing-remitting MS has recently failed on pegylated interferon-beta with a disabling spinal cord relapse and an MRI showing numerous new brain and spinal cord lesions. She had breast cancer diagnosed and successfully treated 7 years ago and has been told by her oncologist that she has no evident detectable disease (NEDD).
After researching the literature she is worried about going onto an immunosuppressive therapy, but realises she needs to be on treatment for her MS.
What would be the most suitable DMT in this situation?
How are we going to counsel her about the malignancy risk associated with each specific MS DMT?
Do you have an answer to these questions? Is there other information you would like before making a decision? Would you like to know my personal recommendation? Would you like more medical fiction on this blog?
