Category: Lab Lessons

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

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

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

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

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

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

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

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

CoI: multiple

#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

Temperature Sensitivity

Are you temperature sensitive? 

In my experience the vast majority of pwMS are affected by changes in temperature; typically it is hot or cold temperature that triggers changes in central nerve conduction velocity that brings on old symptoms. One of my patients reports becoming paralysed if sits outdoors in the sunshine for as little as 30 minutes in the middle of summer. Other report worsening of their cognitive fatigue with relatively minor changes in temperature.  Women post-ovulation raise their body temperatures by about 0.5C; in some woman this enough to incapacitate them. I call this catamenial temperature-related fatigue and it often responds to non-steroidal anti-inflammatories and maybe the reason why aspirin has been shown to improve MS-related fatigue. 

This Korean study below is fascinating. They show that short-term exposure to wide diurnal temperature ranges (DTRs), which have become increasingly common as a result of climate change, is associated with an increased risk of visits to A&E (emergency departments). The was an ~9% change in the odds ratio per 1 °C increase in the diurnal temperature range. If this data is reproduced then it will have a major impact on how we manage patients with MS as global warming ramps up. I suspect the many exacerbations triggered by hot weather may prove to be pseudo-relapses. I suspect this may be the ideal use of serum neurofilament levels; to differentiate relapses from pseudorelapses. Sorting out this old problem may prevent unnecessary MRI scans and more importantly reduce the use of corticosteroids use for possible relapse.

Please be aware that it is not only the ambient temperature that is important, fever can also result in worsening of symptoms. With the COVID-10 pandemic in full swing, I suspect many more pwMS will be monitoring their temperatures as an indicator of infection. I wonder how many of you are doing this? And if yes was it advised by any HCP?  

Byun et al. Association between diurnal temperature range and emergency department visits for multiple sclerosis: A time-stratified case-crossover study. Sci Total Environ. 2020 Feb 25;720:137565. doi: 10.1016/j.scitotenv.2020.137565.

Although multiple sclerosis (MS) has been the leading cause of neurologically-induced disability in young adults, risk factors for the relapse and acute aggravation of MS remain unclear. A few studies have suggested a possible role of temperature changes on the relapse and acute aggravation of MS. We investigated the association between short-term exposure to wide diurnal temperature ranges (DTRs) and acute exacerbation of MS requiring an emergency department (ED) visit. A total of 1265 patients visited EDs for acute aggravation of MS as the primary disease in Seoul between 2008 and 2014 from the national emergency database. We conducted a conditional logistic regression analysis of the time-stratified case-crossover design to compare DTRs on the ED visit days for MS and those on control days matched according to the day of the week, month, and year. We examined possible associations with other temperature-related variables (ambient temperature, between-day temperature change, and sunlight hours). Short-term exposure to wide DTRs immediately increased the risk of ED visits for MS. Especially, 2-day average (lag0-1) DTR levels on the day of and one day prior to ED visits exhibited the strongest association (an 8.81% [95% CI: 3.46%-14.44%] change in the odds ratio per 1 °C increase in the DTR). Other temperature-related variables were not associated with MS aggravation. Our results suggest that exposure to wider DTR may increase the risk of acute exacerbation of MS. Given the increasing societal burden of MS and the increasing temperature variability due to climate change, further studies are required.

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 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

Smouldering away

As you are aware we, or I depending on your perspective, have recently have hit a brick wall trying to convince the MS community that the big unmet need in MS is smouldering disease.

The central hypothesis is that smouldering MS is the real MS. The following YouTube presentation summarises some of the main arguments for the hypothesis.

Your comments will help me make a decision to giving-up working on established MS and to focus on preventive neurology; in particular, preventing MS.

CoI: multiple

DMT churn

Please note that I am so conflicted when it comes to giving advice about DMTs that you need to take what I say and think with a ‘pinch of salt’; including the contents of this post. 

Meaning: To take something with a “grain of salt” or “pinch of salt” is an English language idiom that means to view something with scepticism or not to interpret something literally.

The endless churn or cycling of DMTs is creating problems for MSologists and their patients alike. I am increasingly seeing patients who have been on six or more DMTs. Why? Many switching decisions are related to tolerance issues, unacceptable adverse events, family planning and breakthrough disease activity. However, some churn sadly is due to unrealistic expectations, over- or under-stretched healthcare systems or simply fashion. 

Let’s deal with unrealistic expectations. If you are on DMT x and you are NEDA 1&2, i.e. no relapses or new focal MRI activity, but are still getting worse many patients are being switched in the hope that a different DMT will get on top of smouldering MS. The reality is that we have no data on the efficacy of DMTs in this situation; in fact, we have data from more advanced MS trials that anti-inflammatory DMTs don’t actually make much difference to the pathology driving this stage of the disease. This is why we are pushing so hard for combination therapy trials and the oncologising of MS to create the infrastructure to run multiple, parallel, add-on trials to address smouldering MS. 

Overstretched healthcare systems are incentivising their HCPs to switch patients onto treatments that are less of a burden to the healthcare system, i.e. less monitoring and less hassle for the neurologists and nurse specialists. I have seen this with many patients who are relatively low risk of PML on natalizumab who have been switched off natalizumab to another DMT without having the relative risks, nor the strategies we can use to lower the risk of PML explained to them. In addition, some of the switch therapies, in particular anti-CD20 therapies, come with undefined long-term risks of their own. One of the patients I saw in this situation wants to go back onto natalizumab as she does not feel ‘as well’ on an anti-CD20 as she did on natalizumab. She is complaining that her brain fog has returned. If she had had things explained to her I suspect she would not have switched-off natalizumab.

Switching as a result of under-stretched healthcare systems is the switching of patients onto treatments to increase clinical activity and hence profits. This is more common in fee-for-service healthcare systems but also occurs in the NHS. In short, if you want to maximise your income it is better to have patients on treatments that you can charge extra for, i.e. infusions, monitoring visits, etc. Neurologists are no different from other people; if you create a perverse incentive for doing something we neurologists respond to it, it is human nature.

Fashion refers to the trend that patients often want to be on the newest and coolest DMT. The trend for the latest, brightest and most expensive DMT is often driven by social media influencers; pwMS who promote officially or unofficially DMTs. Switching therapies based on these criteria is not ideal, but some neurologists give-in to their patient’s demands and switch treatments for no apparent treatment benefit. If you are doing well on one treatment moving to another DMT is no guarantee that you are necessarily going to do better on the new drug. In fact, the new treatment may be associated with adverse events and long-term complications that have yet to emerge (known-unknowns on unknown-unknowns).  

When I push the early-diagnosis, early-treatment, high-efficacy-first-line, flipping-the-pyramid philosophy of treating MS, I know that some patients will be harmed for the benefit of the overall population of pwMS. The counter-argument is to maximise the safety of the individual by using a slower-escalation strategy. This strategy, however, comes at a cost for the overall population; i.e. a less favourable group outcome. The path between these two extremes is a narrow one and full of obstacles or cognitive biases that in my opinion get in the way of doing what is best for pwMS. What we can do as neurologists, regardless of what treatment philosophy we subscribe to, is to avoid unnecessary DMT churn. 

Marangi et al. Changing therapeutic strategies and persistence to disease-modifying treatments in a population of multiple sclerosis patients from Veneto region, Italy. Mult Scler Relat Disord. 2020 Feb 10;41:102004. 

BACKGROUND: The availability of new disease-modifying treatments (DMTs) in the last years has changed the therapeutic strategies used in Multiple Sclerosis (MS). We aimed to describe trend in DMTs utilization and persistence to treatment in a large sample of patients attending 10 MS centres from four provinces of Veneto, Italy.

METHODS: Demographic, clinical and DMTs information of patients regularly followed from January 2011 to August 2018 were recorded and analysed. Persistence at 12, 24 months and at last follow-up was assessed by Kaplan Meier survival analysis. Multivariable Cox- proportional hazard model was used to identify predictors of persistence.

RESULTS: Of 3025 MS patients 65.7% were in treatment al last follow-up. Dimethylfumarate (DMF) was the most prescribed single drug among first-line and fingolimod among second-line DMTs. In the cohort of 1391 cases starting any DMT since 2011 12.9% stopped within 6 months, 24% within 12 and 40.3% within 24 months. Disease duration > 5 years at therapy start was predictive of greater risk of discontinuation, while age and sex were not. DMF use was predictive of higher persistence at 12 and 24 months, but not at last follow-up when azathioprine and glatiramer acetate showed the highest persistence compared to other DMTs. Side effects represented the main reason of discontinuation.

CONCLUSION: The use of the new oral DMTs greatly increased since their approval but persistence in the long-term is not better than with old drugs. The treatment choice is still a challenge both for patients and their doctors.

CoI: multiple

Could diet be the new add-on DMT?

Barts-MS rose-tinted-odometer  ★ ★★ ★ ★

I gave my first on using diet as a potential symptomatic and disease-modifying treatment for MS and as a preventative therapeutic strategy in MS, last night.

The symptomatic part of my talk was about food coma and using diet to prevent or reduce the impact of food coma. We are still studying why pwMS are so susceptible to food coma. I suspect it is because they have less cognitive reserve and food coma may interact with other medications to make it such a problem.

The really interesting part of my talk was using caloric restriction (CR), intermittent fasting (IF) or ketogenic (K) diet as a DMT. I suspect the mode of action of all these diets is via ketosis and inducing high levels of circulating β-hydroxybutyrate one of the ketone bodies. Ketone bodies are the source of energy the body uses when we have depleted our sugar stores (glycogen) and are fasting or not absorbing sugar from the gut.

Interestingly, β-hydroxybutyrate works via the hydroxycarboxylic acid receptor 2 (HCA2), which is also known as niacin receptor 1 (NIACR1) and GPR109A. Why is this so important? This is the same receptor that fumaric acid works on. Yes, ketosis works at a cellular level in the same way that dimethyl fumarate (DMF) and diroximel fumarate work, i.e licensed MS DMTs.

Yes, CR/IF/K diet may induce a metabolic pathway that is known to be disease-modifying in MS.

There is an extensive literature, which I discovered about two years ago, showing that β-hydroxybutyrate works via NRF2 and downregulates NFKappa-B, the master inflammatory transcription factor. In other words ketosis, in particular β-hydroxybutyrate promotes programmed cell survival via the NRF2 two pathway and is also anti-inflammatory. β-hydroxybutyrate may even be better than the fumarates as a treatment for MS because it is likely to penetrate the CNS better than oral fumarates.

The corollary of the above could also explain why a processed and ultra-processed high carbohydrate diet is pro-inflammatory. Most people put it down to the pro-inflammatory signals from adipose tissue, but it could be related to the fact that carbohydrates, via insulin, inhibit ketosis and suppress β-hydroxybutyrate levels in the body.

Another nugget of information I found is that metformin also works via NRF2, but not via the HCA2 receptor. This may explain why metformin promotes rejuvenation of oligodendrocyte precursors and is being explored as a potential remyelination therapy in MS.

I have also discovered whilst reading the NRF2 literature that some statins, including simvastatin, activate NRF2. Could this be a potential mode of action of simvastatin in MS?

I didn’t have time to discuss MS prevention last night. However, we think that about 10-20% of the increase in MS incidence may be caused by childhood and adolescent obesity. This is why we are pushing for policy on sugar and a national campaign to tackle this problem.

So when I say I have declared war on sugar, I mean it in more ways than you realise.

Despite observational evidence showing that pwMS do well on CR/IF/K diets, the studies show that they are generally safe. However, we need controlled evidence before promoting these pwMS as a potential adjunctive treatment for MS. The good news is that there are ongoing studies looking into this. The one below is actually using MRI to see if a ketogenic diet has an impact on MRI activity, i.e. the inflammatory component of MS.

Are you up for biohacking your metabolism as a treatment for your MS?

Bahr et al. Ketogenic Diet and Fasting Diet as Nutritional Approaches in Multiple Sclerosis (NAMS): Protocol of a Randomized Controlled Study. Trials, 21 (1), 3 2020 Jan 2.

Background: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults that may lead to progressive disability. Since pharmacological treatments may have substantial side effects, there is a need for complementary treatment options such as specific dietary approaches. Ketone bodies that are produced during fasting diets (FDs) and ketogenic diets (KDs) are an alternative and presumably more efficient energy source for the brain. Studies on mice with experimental autoimmune encephalomyelitis showed beneficial effects of KDs and FDs on disease progression, disability, cognition and inflammatory markers. However, clinical evidence on these diets is scarce. In the clinical study protocol presented here, we investigate whether a KD and a FD are superior to a standard diet (SD) in terms of therapeutic effects and disease progression.

Methods: This study is a single-center, randomized, controlled, parallel-group study. One hundred and eleven patients with relapsing-remitting MS with current disease activity and stable immunomodulatory therapy or no disease-modifying therapy will be randomized to one of three 18-month dietary interventions: a KD with a restricted carbohydrate intake of 20-40 g/day; a FD with a 7-day fast every 6 months and 14-h daily intermittent fasting in between; and a fat-modified SD as recommended by the German Nutrition Society. The primary outcome measure is the number of new T2-weighted MRI lesions after 18 months. Secondary endpoints are safety, changes in relapse rate, disability progression, fatigue, depression, cognition, quality of life, changes of gut microbiome as well as markers of inflammation, oxidative stress and autophagy. Safety and feasibility will also be assessed.

Discussion: Preclinical data suggest that a KD and a FD may modulate immunity, reduce disease severity and promote remyelination in the mouse model of MS. However, clinical evidence is lacking. This study is the first clinical study investigating the effects of a KD and a FD on disease progression of MS.

Trial registration: ClinicalTrials.gov, NCT03508414.

CoI: multiple

Progressive MS is a misnomer

Barts-MS rose-tinted-odometer – zero stars

I am in Milan at the International Progressive MS Alliance Industry Forum Meeting. The aims of the meeting are to:

  1. Discuss challenges understanding and measuring progression and its impact on drug labels
  2. Discuss regulatory issues, opportunities and implications for drug labels and regulatory approvals
  3. Discuss links and opportunities for industry and the Alliance to contribute feedback to the International Advisory Committee on Clinical Trials in Multiple Sclerosis activities on phenotype classification and clinical trials
  4. Share lessons from recent clinical trials/development programs and how they impact the challenges of developing drugs for progression in MS

I have been asked to speak on the implications of disease classification for drug development, regulatory approval and drug labelling. This topic is fine, but it is far removed from people with the disease, which is why I am going to base my talk on case scenarios to illustrate how absurd the current status quo is for pwMS and the wider MS community.

As a pre-read to these case scenarios, I suggest you read a previous post of mine about progressive MS.

Case scenario 1

48-yr old woman
MS x 22 year
Last relapse 8 years ago – lower limb weakness and exacerbation of bladder problems

Annual MRI scans:
Last scan 3  years ago
Marked brain and spinal cord atrophy

Poor gait, now needs to use walking sticks outdoors and can manage only 10-20m; uses scooter outdoors
Bladder and bowel problems  with recurrent UTIs
Significant cognitive impairment

EDSS = 6.5

DMTs: Interferon-beta-1a stopped 3 years

Does this patient have active SPMS?
Does she have active SPMS?

Case scenario 2a

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago / MRI stable

EDSS = 3.0 (stable)

Difficulty running and walking long distance; Fitbit data over the last 3 years showing objective reduction in daily activity

Does this patient have SPMS?
Is the patient eligible for a DMT switch?
Is the patient eligible siponimod?

Case scenario 2b

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago / MRI stable

EDSS = 3.0 (stable)

Difficulty running and walking long distance; Fitbit data over the last 3 years showing objective reduction in daily activity

Labeled as having inactive SPMS
Under NHSE guidelines fingolimod is stopped and 10 weeks later he presents with new onset paraplegia
MRI shows longitudinally extensive myelitis and >30 new Gd-enhancing lesions over the neuraxis

Does this patient have SPMS?
Is the patient eligible siponimod?
What happens if his treatment response is suboptimal on spinoimod?

Case scenario 2c

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago / MRI stable except progressive brain volume loss (0.78% per year over the last 3 years; Icometrix)

EDSS = 3.0 (stable)

Does this patient have SPMS?
Is the patient eligible for a DMT switch?
Is the patient eligible siponimod?

Case scenario 2d

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago

EDSS = 3.0 (stable), but has noticed increasing forgetfulness at work and difficulty using a new software system
T25W & 9HPT stable
SDMT worsening:
2017 = 48 
2018 = 45 
2018 = 41
2019 = 39

Does this patient have SPMS?
Is the patient eligible for a DMT switch?
Is the patient eligible siponimod?

If you work through the logic of each of these case scenarios that are based on real-life examples you will quickly see that the current status quo is not compatible with the biology of the disease and makes very little sense; in other words, classifying MS as three diseases is absurd.

CoI: multiple

Oncologising MS

We have been beating the combination-therapy drum for so long now we have become bored with the concept. Every time we apply for grants to test the concept, be it with pharma or via other traditional funding routes, we get pushback. Either our targets are questioned or the concept of combination therapies is challenged based on the scientific principles underlying the combination being proposed. Then there is regulatory complexity of doing licensing combination trials that makes most Pharma companies put their heads in the sand.

It is obvious that if we want to achieve our aim of getting pwMS to old age so that they can age normally we are going to have to do more than simply tackle inflammation. 

Oncologise is a neologism or new word

I propose oncologising multiple sclerosis and putting in place a national NHS-funded register as part of routine practice, similar to what happens with cancer patients so that everyone can participate in add-on trials of neuroprotectants, remyelination and neurorestoration therapies and any other add-on treatments that we think may work in MS. The latter can include dietary interventions, for example, intermittent-fasting or ketogenic diets. 

Making the case for building a treatment sandwich or pyramid

If the NHS doesn’t fund this I would urge Roche and Biogen to do start with the two biggest blockbusters, i.e. ocrelizumab- and DMF-treated patients and to do this as an international initiative. The real-life trial platform could be run like the oncology platforms in that as soon as you find a combination that is better than the monotherapy (plus placebo) the combination then becomes the standard of care. We would have to implement this with more sensitive outcome measures, possibly brain volume loss, rather than the EDSS which has too many warts to survive much longer. 

Do you think we can oncologise MS? Would you be interested in participating in add-on studies as proposed above? We have ten or more compounds that we could test right now. 

The good news is that I have an ally who works in a large Pharma company who has been chewing the cud with me on this concept and is hopefully going to be able to sell it within his company. If he doesn’t do it I suspect another company may be tempted to take it on.

I gave a talk to general physicians at the Royal College of Physicians (RCP) yesterday afternoon telling them how we have transformed the management of MS. But have we really? To really transform the management of MS we need to cure the disease and then tackle the problem of post-inflammatory neurodegeneration or smouldering MS. The problem we have is that the wider MS community is not necessarily prepared to accept this position and the need for combination therapy add-on studies or the sequential therapy paradigm (induction-maintenance). 

CoI: multiple