Tag: COVID19

#COVIDMS DMT use during the COVID-19 epidemic needs to be more pragmatic

I saw several patients in clinic yesterday and had to speak to many on the phone about what to do about the next course of ocrelizumab and cladribine. It got me thinking.

According to the Italian society of neurology or SIN (Società Italiana di Neurologia) recommendations on the management of patients with MS during the COVID-19 epidemic we should stop dosing. However, the SIN guidelines don’t address the temporal sequence of the COVID-19 epidemic and how the epidemic may evolve.  The SIN guidelines provide relatively straightforward, and I would argue arbitrary, advice on how to manage patients with MS in the short-term, but they don’t address how to manage these patients in the intermediate or long-term and in particular patients with highly active MS. If the public health measures flatten the peak of the epidemic, but extend its tail, the problem of community-acquired COVID-19 infection may be with us for many months and potentially years. Do we stop using these treatments for years?

Over the last few days, I have asked myself are the SIN guidelines compatible with the best interests of our patients or do they represent a knee jerk response to an undefined problem that may not be a problem at all? 

I had a discussion about the COVID-19 epidemic with our renal transplant team who informed me that they are not taking any specific action about the levels of immunosuppression they are providing their transplant patients during the epidemic. Apart from informing their transplant patients to improve their hand and home hygiene, to avoid high-risk travel and unnecessary contacts, to self-isolate if necessary and to reduce contact with the hospital and other medical institutions as much as possible, because they are more likely to be sources of COVID-19. It is business as usual. Nor are they halting their transplant programme. Their argument is that transplanted kidneys and other transplanted organs are too precious not to protect them with relevant immunosuppressive drugs. Why would we not have the same attitude about the brains and spinal cords of our patients with active multiple sclerosis?

I would argue that solid-organ transplant patients are significantly more immunocompromised than pwMS on a DMT. Most transplant patients are on triple immunotherapy, compared to pwMS who are on monotherapy and even then the level of immunosuppression is generally low on MS DMTs. Hence, the mortality risk to an individual on a DMT, who is unfortunate to be infected with COVID-19, maybe actually quite low.  Another hypothesis being considered is that moderate immunosuppression may prevent severe complications associated with COVID-19 infection. The severe pulmonary complications of COVID-19 infection appear to be consistent with ARDS (acute respiratory distress syndrome) caused by an over-exuberant immune response to the virus. As a result of this, several exploratory trials are currently being undertaken in China using immunosuppressants to try and dampen the immune response to the virus. Interestingly, fingolimod the S1P modulator, a licensed DMT for MS, is currently being tested as a treatment for COVID-19 associated ARDS. 

Then there is the virology to take into account. COVID-19 is a new human pathogen, that is likely to have recently crossed species.  COVID-19 will eventually become endemic and hence pose a seasonal risk to patients on immunosuppressive therapies. As it is a small RNA virus with low fidelity it is likely to mutate rapidly making a one-off vaccine only a partial solution. Vaccines take time to be developed, tested and introduced at a population level. Delaying treatment, de-escalating therapy by switching to immunomodulatory DMT, or interrupting dosing of DMTs to wait for a vaccine will delay the adequate treatment of MS. We, therefore, need a pragmatic response to how we manage the potential threat of COVID-19 in individuals with MS. If patients have active MS they need to be treated and managed based on the clinical evidence at hand and hence may need to be treated with higher efficacy DMTs. This will need to be done in the context of appropriate behavioural modifications to prevent exposure to the virus. 

The potential risks posed by each DMT differ and, rather than imposing a blanket rule, decisions regarding treatment should be individualised. For some patients having their MS treated and controlled may be more important than the potential risk of being exposed to and acquiring a severe COVID-19 infection. 

Based on the immunological principles that antiviral responses are mainly driven by T-cells, in particular CD8+ cytotoxic T-lymphocytes, and natural-killer cells and less so, at least initially, by B-cells. Based on these principles there is a hierarchy of immunosuppression of the DMTs. The highest risk will be the immune reconstitution therapies during the depletion phase of the treatment, i.e. HSCT, alemtuzumab (Lemtrada), mitoxantrone (Novantrone) and possibly cladribine (Mavenclad). However, post-immune reconstitution once the total lymphocyte counts have returned to normal the risk of severe viral infections are probably no higher than what would occur in the background population and would be associated with age and other comorbidities. Please note immune reconstitution takes months to years, so if the patient’s last course of treatment was in the last 12-24 months they may still be immunocompromised. As a rough guide if the total lymphocyte count is above 0.8 x 109/L or 800/mm3 they should be able to deal with viral infections reasonably well provided they have not other comorbidities and are relatively young. 

Of the IRTs, cladribine (Mavenclad) should be classed as being of intermediate risk, because it is a relatively poor T-cell depleting agent. T-cells are only depleted post-cladribine by an average of 50% with the CD4+ population being more sensitive than the CD8+ population. In the Phase 3 CLARITY study, viral infections were uncommon post-cladribine and apart from herpes zoster, infections were only slightly more common in cladribine-treated subjects compared to placebo-treated subjects. When viral infections occurred post-cladribine they tended to be mild or moderate in severity. Therefore I think cladribine should be classified as relatively low-risk DMT.

Similarly, anti-CD20 therapies such as ocrelizumab have a minor impact on T-cell counts and are not associated with severe viral infections. In the Phase 3 relapsing-remitting and primary progressive trials infections were more slightly more frequent on ocrelizumab compared to comparator arms (interferon-beta-1a or placebo). Most of these infections were mild and moderate with the severe infections being bacterial in nature (pneumonia, urinary tract infections and cellulitis). Similar to cladribine there was a small risk of herpetic infections, which were mild to moderate and manageable with antiviral agents. I, therefore, feel that anti-CD20 therapies are relatively safe based on their profiles defined in phase 3 trials and we should continue to use them in patients that need them.

Another issue is neutralizing anti-drug antibodies. If you interrupt dosing of ocrelizumab, say after the first course, you may prevent high-zone tolerance from kicking in, i.e. the immunological mechanism that results in the immune system tolerizing itself to foreign proteins. This means that not continuing ocrelizumab therapy may increase the chance of a particular patient developing NABs and being a poor responder to the drug when it is recommenced.

Clearly any decision to start a DMT during the COVID-19 epidemic will need to be taken carefully and will depend on the state of the COVID-19 epidemic, not only in the particular country concerned, but in the specific area, the patient lives and is being treated in. For example, aggressive public health steps to contain the spread of the virus locally may make it relatively safe for a patient to start an immunosuppressive therapy. My concern is that the COVID-19 epidemic may trigger a large number of neurologists and patients to reconsider their treatment strategy and choice of initial DMT and to opt for less effective immunomodulatory DMTs. A change in treatment strategy driven by COVID-19 needs to be carefully considered. The COVID-19 epidemic in all likelihood will be short-lived and it would be unfair to patients treated during the epidemic to be disadvantaged in the long term regarding the management of their MS. We have spent an extraordinary amount of time and effort to activate the MS community; to get across the principle that ‘time is brain’, to treat MS proactively to a target of no evident disease activity (NEDA) and more recently to flip the pyramid and use higher efficacy treatments first line. These treatment principles are evidence-based and should not be thrown out in the context of a potential but yet undefined risk to our patients that in my opinion is being overemphasised; please remember we have no data on COVID-19 infection in patients with MS on DMTs. 

Is there anything we learn from renal transplant physicians? Yes, with the possible exceptions of alemtuzumab, HSCT and mitoxantrone, which cause quite potent short-term immunosuppression, I think it should be business, or decision-making, as usual taking into account the caveats above with a major emphasis on reducing the risk of our patients acquiring the infection in the first place. 

Groupthink and knee jerk responses are not necessarily in the best interests of our patients. So after discussing the evidence with many of my patients yesterday, we are cautiously going to continue ocrelizumab and cladribine dosing. In other words, personalised decision-making and a pragmatic approach are required. What is decided for one patient may not necessarily be right for another patient; do you agree with me? 

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 Will COVID-19 mutate?

Human coronaviruses are predominantly associated with respiratory tract infections. This group of viruses includes viruses that cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and now the COVID-19 pandemic.

One human coronavirus HCoV-OC43 is generally associated with mild upper respiratory tract infections, although it has been shown to have neuroinvasive properties. Studies in mice have shown that HCoV-OC43 can infect neurons and cause encephalitis and has also been shown to cause persistent infections in human neural-cell lines.

There are case reports that have identified HCoV-OC43 RNA in the cerebrospinal fluid or brain of children with acute disseminated encephalomyelitis and acute encephalomyelitis (see below).

Why are these observations important? They are important because it suggests that coronaviruses are potentially neurotropic and hence can infect the central nervous system. As coronaviruses are RNA viruses they have low fidelity, i.e. their reproduction results in many variants or mutations. The so-called wild-type strain tends to mutate very rapidly and hence may produce neurotropic strains quite quickly. The latter is particularly important in the context of natalizumab and potentially fingolimod and other S1P modulators.

As natalizumab blocks immune surveillance of the CNS, a person on natalizumab who develops a COVID-19 encephalitis would be in danger of major complications of the infection and possibly succumbing to the infection. The latter is analogous to PML, which is also viral encephalitis, and herpes-simplex and varicella -zoster encephalitis and CMV retinitis that have all been described in people with MS on natalizumab. 

The reason why these complications happen on natalizumab is that natalizumab blocks trafficking of anti-viral lymphocytes into the central nervous system and so if a virus gets into the CNS it will cause damage unchecked by the immune system. The EMA’s summary of product characteristics (SmPC) for natalizumab is very clear on this issue:

Infections including other opportunistic infections 

TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving TYSABRI (see section 4.8). If herpes encephalitis or meningitis occurs, the medicinal product should be discontinued, and appropriate treatment for herpes encephalitis or meningitis should be administered. Acute retinal necrosis (ARN) is a rare fulminant viral infection of the retina caused by the family of herpes viruses (e.g. varicella zoster). ARN has been observed in patients being administered TYSABRI and can be potentially blinding. Patients presenting with eye symptoms such as decreased visual acuity, redness and painful eye should be referred for retinal screening for ARN. Following clinical diagnosis of ARN, discontinuation of TYSBABRI should be considered in these patients. Prescribers should be aware of the possibility that other opportunistic infections may occur during TYSABRI therapy and should include them in the differential diagnosis of infections that occur in TYSABRI-treated patients. If an opportunistic infection is suspected, dosing with TYSABRI is to be suspended until such infections can be excluded through further evaluations.

What to do about this knowledge in the current COVID-19 pandemic is very difficult. Professor Julian Gold, an HIV and infectious disease consultant in our group, is adamant that we need to relay this information to our patients and let them make the decision if they want to stop natalizumab or fingolimod. However, as stopping these agents can result in rebound MS disease activity it would be advisable for these patients to switch to an alternative or safer DMT, i.e. interferon-beta, glatiramer acetate or teriflunomide. Professor Gold favours interferon-beta or teriflunomide as they have been shown to have antiviral effects. 

As there is no consensus on this I am doing a survey via the MS Academy to find out what the wider MS community of HCPs feels about this and other issues. Just maybe the wisdom of the crowd will be better than an individual or small group opinion. 

In the event of widespread COVID-19 epidemic, the logistics of derisking natalizumab and fingolimod is this way may not be feasible. A better way of managing this problem is reverse quarantine, i.e. at-risk patients stay on natalizumab or fingolimod and self-isolate at home to prevent themselves from becoming infected with the virus. 

The other issue I have already raised is when a vaccine emerges for COVID-19 pwMS may want to be on a DMTs that allows to receive the vaccine and mount a good response to the vaccine. Some DMTs blunt the vaccine responses.

I hope you appreciate that formulating advice when there is no evidence base is not easy. At the moment whilst the epidemic has yet to show its true extent in the UK I would advise MS patients on natalizumab or fingolimod to continue with treatment for now but to be extra-vigilant about hygiene measures. This advice may change or it may need to be personalised.

Finally, as soon as the ABN and MS Academy produce consensus guidelines I will post them on the blog. The problem about consensus is that it is often a compromise and in the absence of data may not be the best advice.

Yeh et al. Detection of Coronavirus in the Central Nervous System of a Child With Acute Disseminated Encephalomyelitis. Pediatrics January 2004, 113 (1) e73-e76.

We present a case in which human coronavirus was detected in the cerebrospinal fluid of a child presumed to have acute disseminated encephalomyelitis. In murine models, coronavirus has been found to cause a chronic demyelinating condition that resembles multiple sclerosis. Additionally, there is in vitro evidence of human coronavirus’s ability to infect neural cells. This case report provides additional support for the hypothesis that coronavirus may be an important etiologic factor in the pathogenesis of demyelinating disease in humans.

Morfopoulou et al. Human Coronavirus OC43 Associated with Fatal Encephalitis. N Engl J Med 2016; 375:497-498.

Excerpts:

….. Here we report the use of deep sequencing of a brain biopsy sample obtained from an 11-month-old boy with severe combined immunodeficiency who had symptoms of viral encephalitis with negative results on conventional diagnostic polymerase-chain-reaction (PCR) assay. 

….. The boy underwent unconditioned cord-blood transplantation, which resulted in T-cell engraftment. Nonetheless, his condition continued to deteriorate, and he died 1.5 months after receiving the transplant. RNA sequencing of a brain biopsy sample obtained 2 months after the onset of symptoms showed the presence of human coronavirus OC43 (HCoV-OC43), which was subsequently confirmed on real-time PCR (threshold cycle, 24) and brain immunohistochemical analysis. 

CoI: multiple

N.B. MOUSEDOC HERE So AS YOU KNOW THERE ARE ALREADY MUTATIONS IN THIS VIRUS THE ORIGINAL S VARIANTAND THE L VARIANT

#COVIDMS The Italians step-up to take action over COVID-19

As you are aware Northern Italy is one of the European epicentres of the coronavirus / COVID-19 pandemic. To address the concerns of MS healthcare professionals the Milan group have produced guidelines for managing DMTs in their patients. Fortunately, we have a large number of Italians in our group (‘The Blizard Little Italy’) who, with Dr Saul Reyes (ECTRIMS Fellow), helped translated the guidelines for us.

Italian recommendations on the management of MS patients during the COVID-19 epidemics

These are recommendations made by Neurologists and Infectious diseases specialists whilst we have no evidence-based data at present. 

Treatment of MS patients

Given the lack of knowledge or data on the COVID-19 disease course in MS patients receiving DMTs, at present there is no recommendation to stop the different DMTs and therefore expose MS patients to the risk of MS exacerbations. We, therefore, recommend continuing the current DMT specifically with: 

1. First-line DMTs (Beta-interferons, Glatiramer acetate, Teriflunomide or Dimethyl fumarate). These DMTs can be prescribed as usual.

2. Fingolimod. 

3. Natalizumab.
 
For ‘lymphodepleting’ DMTs: Any decisions about these DMTS should be made based on individual circumstances. 

Temporarily delay the start of lymphodepleting DMTs such as Ocrelizumab, Alemtuzumab, Rituximab or Cladribine. 

Temporarily delay (between 6 and 12 months depending on the DMT) re-dosing of Alemtuzumab, Ocrelizumab and Cladribine. This decision should be made based on individual factors such as disease severity and disease activity.

For anti-CD2O DMTs it is recommended to delay next dose even beyond 6 months if CD19+ and CD20+ lymphocyte counts are severely decreased at the time the next dose is due. 

Some special considerations: for patients who have already received the first dose of the first cycle, it is recommended to give the second dose (i.e. complete the first cycle) and ‘extra precautions’ should be taken. 

Patients with confirmed COVID-19 infection: Withheld any first or second-line DMT until clinical resolution and/or approval to continue treatment by an infectious diseases specialist (given the potential antiviral activity of beta-interferons documented in the literature, for patients receiving treatment with beta-interferons the decision about continuing treatment resides on the treating neurologist). 

Symptoms of potential COVID-19 infection: fever, dry cough and asthenia. 

What to do in the event of COVID-19 symptoms?
Instruct your patients no to attend A&E services to avoid overcrowding them and further spreading of the virus. Instruct your patients to call the local emergency number, describe their symptoms and wait for instructions. 

Evaluate the temporary withdrawal of current DMT based on the guideline provided above.  

Recommendations for MS patients and healthcare professionals at MS centres:

If possible, avoid crowded places such as cinemas, theatres, schools, etc. 

In high risk, areas restrict access to MS centres to MS patients only. 

For patients on immunosuppressive infusion therapies, the use of protective surgical-grade masks is recommended. 

If travelling long distances or using public transport is absolutely necessary, it is recommended the use of protective masks and hand sanitizing (particularly for patients on Fingolimod, Alemtuzumab, Ocrelizumab, Cladribine or Rituximab).

If possible, work from home. 

Good personal hygiene is always important, specifically, it is recommended to wash your hands frequently. These recommendations are provided as a guideline only, please always refer to your local government advice.

These recommendations are likely to change depending on the evolution of the epidemics. 

#COVIDMS COVID-19 and DMTs

The coronavirus/COVID-19 pandemic is getting people with MS (pwMS) who are on a DMT to rightly question whether or not their immune systems are competent to deal with a COVID-19 infection. Unless you are on interferon-beta, glatiramer acetate or teriflunomide, the so-called immunomodulatory therapies, your immune systems are likely to be compromised and hence you are at risk of getting more severe COVID-19 infection or secondary complications of an infection. 

Based on the immunological principles that antiviral responses are mainly driven by T-cells and natural-killer cells and less so, at least initially, by B-cells there is a hierarchy of immunosuppression on the DMTs. At the top of the list must be the immune reconstitution therapies during the depletion phase fo the treatment, i.e. HSCT, alemtuzumab [Lemtrada] and cladribine [Mavenclad]. For the maintenance treatments, I would rank them in descending order as being natalizumab [Tysabri], S1P modulators (fingolimod [Gilenya] / siponimod [Mazent] / ozanimod / ponisemod), anti-CD20 (ocrelizumab [Ocrevus] / rituximab / ofatumumab / ublituximab) and in the rear the fumaric acid esters (DMF [Tecfidera] / diroximel fumarate [Vumerity]). With the fumaric acid esters, this low ranking will not apply applies if your lymphocyte counts are low, i.e. generally lower than 0.8×109/L or 800/mm3. 

I have put natalizumab at the top of the list as we don’t know how neurotropic this virus is. If it is neurotropic, i.e. has the ability to infect the brain natalizumab is risky. Natalizumab creates a compartment that is protected from the immune system and hence puts people at risk of COVID-19 encephalitis.

Because of the coronavirus/COVID-19 pandemic should I stop my DMT? No, you should not. My advice is for you to discuss this with your HCP. There are many factors that need to be taken into account, in particular, the risk of you being exposed to COVID-19 in your country. The risk can be mitigated by hygiene measures and avoiding high-risk travel and places and contacts that may expose you to the virus. The latter strategy will become more difficult as the pandemic spreads and more people in the general population become infected and shed the virus. 

Just stopping MS DMTs, particularly natalizumab and S1P modulators, could result in MS rebound disease activity that is potentially serious. 

Because of the coronavirus/COVID-19 pandemic should I delay further infusions with natalizumab and ocrelizumab? No, you should not make this decision yourself. My advice is for you to discuss this with your HCP. If you are going to stop natalizumab you need to transition yourself onto another DMT. Ocrelizumab and the other anti-CD20 therapies are slightly different in that their treatment effect takes many months and possibly years to wear off so you have more time to think.

As I am about to start cladribine, fingolimod, siponimod, alemtuzumab, natalizumab or ocrelizumab, should I delay treatment? This will need to be discussed with your HCP and the advice will depend on the state of the COVID-19 epidemic in your country or area. For example, if you live in Milan the advice is not to start these treatments. I suspect the COVID-19 epidemic may trigger a large number of pwMS who have yet to start treatment to reconsider their choice of DMT, based on the potential risks of getting a more severe infection on immunosuppressive therapies.

I have been treated with an IRT several years ago am I at risk of infection with coronavirus/COVID-19? Yes, you are. The risk of becoming infected will be no different from that in the general population. 

The advantage of the so-called IRTs (HSCT, alemtuzumab and cladribine) is that they allow immune reconstitution, which refers to the restoring of your immune system to a state of competency after a cycle, or cycles, of depletion. Immune competence in the context of an IRT refers to the ability of the immune system to respond to infections, in particular opportunistic infections, mount an antibody response to vaccines and tumour surveillance. This has been best shown in the context of hematopoietic stem cell transplantation (HSCT) but is likely to be the case for alemtuzumab and cladribine. Please note reconstitution takes years, so if your last course was in the last 12-24 months you may still be immunocompromised. You can get a rough idea of the state of your immune system by looking at your total lymphocyte count, ideally, you want this to be above 1.0 x 109/L or 1000/mm3. 

Should I switch my DMT to interferon-beta, glatiramer acetate of teriflunomide? This may seem like a logical thing to do, but it is seldom that simple. Most pwMS are on a higher efficacy DMT because they have failed these treatments in the past. Therefore de-escalating your therapy to a previous DMT you have failed may result in your MS getting worse. 

Teriflunomide is an interesting option because it has been shown to have broad antiviral activity and hence has the potential to protect pwMS against COVID-19 infection and its complications. I would propose Sanofi-Genzyme doing urgent studies to test this hypothesis. The Coronavirus pandemic will take months to years to play out and knowing that teriflunomide has anti-coronavirus activity will be useful information for the MS community. 

In summary, there are no easy answers. The pandemic is evolving at a rapid rate and country-specific information will emerge depending on the state of the epidemic in each country. At the same time, there are many anti-viral studies been run and there is a race on to develop a vaccine. My money would be on a DNA-vaccine winning the race, because of the ease of production of these sorts of vaccines. But as always there will be regulatory hurdles to overcome and hence any vaccine studies will be months away.  So don’t rely on there being a vaccine or effective anti-viral drug anytime soon.

Hill-Cawthorne et al. Long Term Lymphocyte Reconstitution After Alemtuzumab Treatment of Multiple Sclerosis. J Neurol Neurosurg Psychiatry, 83 (3), 298-304 Mar 2012.

Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined.

Methods: The lymphocyte reconstitution (n=36; 384 person-years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis.

Results: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10(9) cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10(9)/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10(9) cells/l) and CD4 lymphocytes (LLN ≥0.4×10(9) cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person-years of follow-up.

Conclusions: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long-lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.

CoI: multiple

#COVIDMS COVID-19 pandemic changes the rules

I am at an MS meeting in Frankfurt and was speaking to an Italian neurologist about the COVID-19 or coronavirus pandemic and he informs me that in Milan, the epicentre of the Italian outbreak, they have stopped dosing their MS patients with ocrelizumab, alemtuzumab and cladribine until the epidemic has passed.

Interestingly, they are not stopping fingolimod, which leaves a whole cohort of pwMS at high risk of complications from COVID-19 if they get infected. As I have said in a previous post that the risk of complications from COVID-19 is likely to be higher on natalizumab as well; natalizumab blocks trafficking of lymphocytes into the CNS and gut. These compartments may allow the virus to escape the immune system and cause damage or prolong the infection.

In my post from two days ago, I added a postscript that predicted the Italian response to the virus, i.e. once COVID-19 becomes established in the community and person-to-person spread becomes more common and the source of infection(s) can’t be traced, which is happening in Italy, the public health advice will change. In this situation reverse quarantine becomes necessary, i.e. high-risk individuals need to take extra precautions, potentially self-isolating themselves so as not expose themselves to the virus. Not dosing certain DMTs, and stopping other DMTs, is part of this containment strategy.

Please note this is not necessary in the UK as all the cases have been linked to a clearly identifiable source.

John Hopkins CSSE

John Hopkins has put together a very useful website to track the pandemic in real-time. You may want to refer to this for up to date information on what is happening in your country.

The reality of the situation is a known unknown; it is only a matter of time before someone with MS, who is immunosuppressed, will be infected and succumb to the infection. It is the MS community’s responsibility to try and prevent this from happening.

CoI: multiple

#COVIDMS Coronavirus creates an opportunity for teriflunomide

Should I switch to teriflunomide? 

Please don’t panic! The coronavirus or COVID-19 pandemic is a problem but needs a calm and considered public health approach, which is happening in the UK. At the moment the general public, including pwMS, are overreacting.

Another patient emailed me yesterday to inform me they are going to stop their ocrelizumab and asked what the consequences will be. In the short-term very little, but if you decide to stop ocrelizumab it may provide an opportunity to test a hypothesis.

The treatment effect of ocrelizumab lasts many months and probably years after stopping the treatment. In the phase 2 ocrelizumab extension study, the group of patients who had been treated with ocrelizumab had no disease activity 18 months later. The latter is what underpins one of our proposed treatment arms in the ADIOS study and suggests that anti-CD20 could be used in a similar way to IRTs (immune reconstitution therapies), i.e. alemtuzumab, cladribine and HSCT. 

What about safety? B-cells and b-cell responses don’t return immediately after stopping ocrelizumab. They take about 6-12 months to reconstitute. The B-cells that return are not memory B-cells, but initially naive cells that later mature with memory B-cells taking several years to reappear. The bigger issue is circulating immunoglobulin levels. With time as more patients develop hypogammaglobulinaemia on anti-CD20 therapies, the serious infection risk will go up. This is clearly seen in the Swedish rituximab data (see below), which shows that by 6 years approximately 50% of rituximab-treated patients have had a serious infection. This will almost certainly occur with ocrelizumab and ofatumumab and the other emerging anti-CD20 therapies. 

Figure from Luna et al. 2019

Therefore stopping ocrelizumab, rituximab, ofatumumab or another anti-CD20 is not going to reverse your immune defects overnight; it will take months and possibly years to have a fully functional and reactive B-cell and plasma cell repertoire. Some argue that you can reverse these defects with immunoglobulin replacement therapy. Yes and no! Yes, in terms of broad-spectrum population-type immunity, but no in terms of antibodies against new infectious agents such as COVID-19. For the latter to be covered you would need immunoglobulin from COVID-19 exposed survivors. I suspect Chinese medical entrepreneurs will be working on this strategy already. Organism-specific, in this case, COVI-19 specific, hyperimmune globulin therapy is a well-trodden path and may yet prove to be an effective treatment strategy in managing high-risk COVID-19 infected patients as an emergency.

The latter may be relevant in the context of COVID-19 as the pandemic will play out over months to years. Similarly, if a COVID-19 vaccine is developed you may want to be in a position to maximise your benefit from any future vaccine by not being on an anti-CD20 or other immunosuppressive therapy.

What should you do if you want to derisk your immunosuppression, increase your vaccine responsiveness and keep your MS in remission? This is where the immunomodulators will see a resurgence, in particular teriflunomide. I have hypothesised in the past that teriflunomide is the ideal maintenance therapy post-induction with an anti-CD20; I called this the iTeri study. My grant application for the iTeri study was rejected by Genzyme-Sanofi; I suspect because the patent-life of teriflunomide was too short to make this study worthwhile. However, the iTeri data may emerge spontaneously from real-life data as a result of the COVID-19 pandemic. Let’s say 5,000-10,000 pwMS derisk their treatment from an anti-CD20 onto teriflunomide the data will emerge from registers on how good teriflunomide in keeping these people in remission. 

Please be aware that I have always referred to teriflunomide as the dark horse DMT; COVID-19 may prove to be the stimulus that allows teriflunomide to run free outside its small paddock.

Gustavo Luna et al.  Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies. JAMA Neurol 2019; Oct 17 (online)

Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.

Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.

Design, setting, and participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.

Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon-beta and GA.

Main outcomes and measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.

Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).

Conclusions and relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.

CoI: multiple

Pandemic

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: 

  1. A long asymptomatic period during which infected people shed the virus and are infectious
  2. Asymptomatic shedders who don’t get ill
  3. An estimated R0 (r-zero) of 3-5, which is an estimate of how many people or contacts that an infected person infects 
  4. The identification of superspreaders; individuals who seem to be able to infect a large number of people
  5. 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
  6. 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
  7. 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.

Infographic: The Biggest Human Migrations in the World | Statista You will find more infographics at Statista

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.

CoI: multiple