News and events – Page 7 – Prof G's MS Blog Archive

#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 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

High-dose biotin disappoints

Disappointing news 🙁

MedDay has just announced the second Phase III trial, SPI2, of high-dose biotin (MD1003) is negative. I am sure many people with progressive MS will be disappointed. However, this trial supports why we need to blinded, randomised, controlled trials; i.e. to test hypotheses. Let’s hope some lessons will be learnt from the trial data that will inform future trial design in more advanced MS.

I would like to thank all the people with progressive MS who participated in this study and all the diligent staff for making it happen. It may be a disappointing result, but without negative trial results, we don’t learn.

CoI: I am a member of SPI2 trial steering committee and our centre participated in the trial.

#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.

CoI: multiple

Dodging COVID-19 to fly to Copenhagen

I arrived late last night in Copenhagen to give a keynote lecture at their Danish MS Society’s annual conference. Copenhagen airport was eerily quiet; COVID-19 is clearly having a dramatic effect on flying.

I was asked to give an overview of emerging treatment targets and outcomes in MS. My focus is going to be smouldering MS. I had to cut the section on prevention from my talk; prevention always seems to be short-changed. Maybe not for much longer?

You can download the slides from my DIY-slideshare site.

CoI: multiple

#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 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.

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