Tag: NMSS

#MSCOVID19: cladribine is being unfairly tarnished with alemtuzumab’s brush

Barts-MS rose-tinted-odometer: ★★★★★

I think the North American MS community have made some mistakes with their COVID-19 vaccine recommendations, in particular, the NMSS COVID-19 vaccine guidelines for cladribine. In view of the immunology of cladribine’s mode of action and new data that is emerging, I would suggest the NMSS considers updating its guidelines. 

Lemtrada and Mavenclad

If you are about to start Lemtrada or Mavenclad, consider getting the Pfizer BioNTech or Moderna COVID-19 vaccine so that the second vaccine injection is done 4 weeks or more prior to starting Lemtrada or Mavenclad. If you are already taking Lemtrada or Mavenclad, consider administering the vaccine injections starting 12 weeks or more after the last Lemtrada or Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose2. When possible, resume Lemtrada or Mavenclad 4 weeks or more following the second vaccine injection. This suggested scheduling is not always possible and getting the vaccine when it becomes available to you may be more important than timing the vaccine with your DMT. Work with your MS healthcare provider to determine the best schedule for you.

Lumping cladribine and alemtuzumab together as being immune-depleters of the same ilk is simply wrong. Alemtuzumab is more of a sledgehammer and is relatively non-selective in depleting both T-cells and B-cells and it also hits innate immunity, in particular monocytes. This is why there is a major infection signal (e.g. listeriosis) with alemtuzumab in the 4-6 weeks after each course of treatment. The latter does not occur with the doses of cladribine we use to treat people with MS.

In comparison, the mode of action of cladribine is very subtle and more in keeping with a selective B-cell depleting agent. Cladribine depletes B-cells by about 85-90% and hits mainly memory B-cells, in other words, large numbers of naive B-cell persist in the peripheral blood. We think as memory B-cells are being killed fresh naive B-cells are being released from the bone marrow. This is important because it is the naive B-cell population that is required to make new antibody responses to vaccines. 

Cladribine only depletes T-cells by about 50% a level that in general is not sufficient to put patients at risk of opportunistic infections or even viral infections. When we recently reanalysed all of the cladribine safety data there was no novel or new exogenous (from outside the body) viral infection signal. The only viral infection signal we saw was zoster or shingles, i.e. a reactivation of a latent virus, which is common and occurs with all immunosuppressive therapies. 

Another very big difference between cladribine and alemtuzumab is the fact that cladribine leaves the innate immune system intact, which is important for fighting infections and for processing vaccine antigens and presenting them to the immune system. 

Another factor that is different is the temporal profile of immunodepletion that occurs with alemtuzumab and cladribine. Alemtuzumab causes rapid cell lysis with its effect noticeable in hours to days; in other words, peripheral blood lymphocyte and monocyte counts are depleted to very low levels (nadir) very quickly. In comparison, cladribine works by triggering apoptosis of cells and lymphocytes die slowly over weeks to months reaching a nadir at about 3 to 4 months after each course. Therefore for the NMSS guidance to say “consider administering the vaccine injections starting 12 weeks or more after the last Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose” is actually recommending giving the vaccine from the start of the nadir. 

Unlike alemtuzumab, I think the timing of vaccination in patients treated with cladribine is unlikely to make much of a difference because both the afferent (antigen processing and presentation) and efferent (B-cells/antibodies and T-cells) limbs of the immune system is intact, i.e. there is enough hardware or cells at all times post cladribine to make an immune response. Saying this the summary of product characteristics of cladribine clearly states that live vaccines should be avoided until the immune system has reconstituted and the cells counts have returned to normal. Please note this refers to live vaccines and doesn’t apply to the currently licensed COVID-19 vaccines, which are not live attenuated vaccines or LAVs.

The good news is that the above predictions are being borne out by some real-life flu and VZV vaccine data in cladribine-treated patients that have been presented at ACTRIMS this week. My interpretation of this data is that regardless of when a vaccine is administered in patients on cladribine the appear to mount a good antibody response. I agree the number of subjects studied is small and no subject has had grade 4 lymphopaenia (<200/mm3), but these data at least confirm what you would expect to happen based on immunological principles. 

My advice, therefore, remains the same for pwMS on DMTs; during the height of the pandemic having some immunity to SARS-CoV-2 is better than having no immunity. This is why you should get vaccinated ASAP. If you live in an environment where the background risk of COVID-19 is low then you may want to optimise the timing of your vaccine, when you are next dosed with an immunodepleting therapy or when you start or switch therapies.


Roy & Boschert. Analysis of Influenza and Varicella-Zoster Virus Vaccine Antibody Titers in Patients with Relapsing Multiple Sclerosis Treated with Cladribine Tablets. P059 – ACTRIMS 2021

Background: There is a lack of data available to determine the effect of cladribine tablets (CladT) on the antibody response to vaccination in patients with relapsing multiple sclerosis (MS).

Objectives: To investigate the immunoprotective response to seasonal influenza and varicella-zoster virus (VZV) vaccination in patients treated with CladT (3.5mg/kg over 2 years) for relapsing MS.

Methods: Blood samples collected during the MAGNIFY-MS study (NCT03364036) from 9 patients with relapsing MS treated with CladT who received seasonal influenza (n=8) or VZV vaccinations (n=1; Shingrix) as a standard of care were retrospectively analyzed. Two control blood samples (baseline sample before starting CladT and closest sample available just before vaccination) and two post-vaccination blood samples (closest sample available after vaccination) were examined. Quantitative antibody titers in response to the seasonal influenza and VZV vaccine were measured by hemagglutination inhibition (HAI) assay and Enzyme-Linked Immunosorbent Assay (ELISA), respectively. The seroprotection titer level for the seasonal influenza vaccine is considered ≥40, and was ≥100 IU/L for the VZV vaccine.

Results: Influenza: All patients vaccinated against influenza A and B during year 1 or 2 of CladT treatment retained seroprotection titers of ≥40 in post-vaccination samples across all strains present in the vaccine administered. The number of seropositive patients (HAI ≥40) with a ≥4-fold and ≥2-fold increase against at least 1 strain in post-vaccination titers were 3/8 and 7/8, respectively. VZV: Post-vaccination antibody titers were 40-fold increased over the protective titer at all time points (titers >4748 IU/L).

Conclusions: In this small retrospective investigation, post-vaccination antibody titers in patients treated with CladT for relapsing MS remained at levels that offer protective immunity against seasonal influenza and VZV.

Wu et al.  Evaluating the Impact of Cladribine Tablets on the Development of Antibody Titers: Interim Results from The CLOCK-MS Influenza Vaccine Substudy. P071 ACTRIMS 2021

Background: Cladribine tablets have been approved in more than 80 countries for the treatment of relapsing forms of multiple sclerosis (RMS), and are hypothesized to function as an immune reconstitution therapy with potential to cross the blood-brain barrier. The CLOCK-MS study (cladribine tablets: collaborative study to evaluate impact on central nervous system biomarkers in multiple sclerosis), is a 24-month, open-label, randomized, multicenter, collaborative Phase IV biomarker research study. The COVID-19 pandemic, and pending vaccine availability, have raised important questions around the impact of MS disease modifying therapies on vaccine efficacy.

Objectives: To evaluate the potential impact of prior treatment with cladribine tablets on the development of antibody titres post-influenza vaccination via a sub-study of CLOCK-MS.

Methods: The CLOCK-MS main study will enroll approximately 50 subjects age 18-65, diagnosed with relapsing-remitting MS or active secondary progressive MS, who had inadequate response to, or were unable to tolerate, an alternate drug indicated for the treatment of RMS. Study participants who have taken at least one dose of cladribine tablets and are planning to obtain one standard-of-care influenza vaccine are eligible to take part in the sub-study if they consent to blood draws. Blood sampling will occur 1) 3 Weeks Pre-Vaccine (within 21 days prior to obtaining a standard of care vaccine), 2) 4 Weeks Post-Vaccine (+/- 7 days), and 3) 6 Months Post-Vaccine (+/- 7 days). Measurements of antibody responses will be performed.

Results: So far 5 patients have been enrolled in this sub-study and had initial titers drawn. All patients fulfilled the per-label requirements for vaccination after cladribine tablets treatment. Initial results at Week 4 post-vaccination will be presented.

Conclusions: The impact of cladribine tablets, a lymphocyte-lowering agent, on the immune system’s ability to develop antibodies in response to a vaccine has not yet been studied. These results are expected to provide preliminary observations around the impact of cladribine tablets on influenza vaccine efficacy in patients with RMS.

CoI: multiple

Twitter: @gavinGiovannoni                                      Medium: @gavin_24211

HSCT makes the recommended list

Barts-MS rose-tinted-odometer: ★★★★★

Good news for people with MS living in the US. The National Multiple Sclerosis Society is acknowledging that autologous hematopoietic stem cell transplant (AHSCT) is an effective treatment for MS as is recommending  AHSCT a useful treatment option for pwMS who have substantial breakthrough disease activity despite treatment with high-efficacy DMTs or have contraindications to high-efficacy disease-modifying therapies. The acknowledge that pwMS younger than 50 years with shorter durations of disease (<10 years) have the most to gain from AHSCT. 

The big question is will insurers and national funders pay for HSCT in the US based on this recommendation or will they still need FDA approval? 

The good news for pwMS living in the UK is that the NHS already covers the cost of HSCT and MS is on the list of approved autoimmune diseases for treatment with HSCT. The problem in the UK is not necessarily the access to the treatment, but to get risk-averse neurologists to refer pwMS for the procedure or am I wrong?

Miller et al. Autologous Hematopoietic Stem Cell Transplant in Multiple Sclerosis Recommendations of the National Multiple Sclerosis Society. JAMA Neurol. Published online October 26, 2020. doi:10.1001/jamaneurol.2020.4025

Importance:  Autologous hematopoietic stem cell transplant (AHSCT) for multiple sclerosis has gained increasing interest in recent years. Despite the availability of many US Food and Drug Administration–approved disease-modifying therapies, some patients do not respond adequately and others may have very early aggressive disease that prompts consideration of alternative, highly effective, long-lasting therapy. The National Medical Advisory Committee of the National Multiple Sclerosis Society has reviewed recent literature on AHSCT for the purpose of making recommendations about its use based on current knowledge, as well as pointing out areas of controversy and issues requiring further research.

Observations:  Studies on AHSCT have repeatedly demonstrated high efficacy and a durable outcome in people with relapsing multiple sclerosis. Recent studies have shown considerable improvement in the safety of the procedure, with much lower mortality rates than were reported earlier. Consensus is emerging about the characteristics of the best candidates for the procedure. Questions remain about the ideal protocol, particularly about the best conditioning regimen to be used to kill immune cells. Larger randomized clinical trials are needed to address the question of whether AHSCT has advantages over the most efficacious disease-modifying agents currently available. One such trial (Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis [BEAT-MS) is currently in progress.

Conclusions and Relevance:  The National Multiple Sclerosis Society believes that AHSCT may be a useful treatment option for people with relapsing multiple sclerosis who demonstrate substantial breakthrough disease activity (ie, new inflammatory central nervous system lesions and/or clinical relapses) despite treatment with high-efficacy disease-modifying therapy or have contraindications to high-efficacy disease-modifying therapies. The best candidates are likely people younger than 50 years with shorter durations of disease (<10 years). The procedure should only be performed at centers with substantial experience and expertise. Ideally, recipients of the procedure should be entered into a single database, and further research is needed to establish ideal cell mobilization and immune-conditioning regimens.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

Re exercise in MS: should we be flogging a dying horse?

Barts-MS rose-tinted-odometer ★★★ 

I am at the NMSS’ Pathways to Cures think tank where exercise is a major theme in terms of restoring lost function. A lot of discussions have been about how we motivate and get pwMS to exercise. Some suggested using motivational interviewing techniques and behavioural psychology to motivate and nudge pwMS to exercise. The elephant in the room is that some people simply don’t like exercise. Are you one of them?

Not many people know that your participation in exercise is largely driven by genetics. It is clear from the twin study below that genetic variation is important in relation to individual behaviour when it comes to exercise. Heritability of exercise participation in males and females was similar and ranged from 48% to 71%; this may explain why you love or hate exercise. At the moment we don’t know what this heritability in relation to exercise is due to. As the investigators’ point out in their conclusion that it may ‘involve genes influencing the acute mood effects of exercise, high exercise ability, high weight loss ability, and personality’. 

One of the other aspects of exercise that was discussed was its biology, in other words how does exercise work. If we can work this out we could potentially explore drugs to mimic exercise. The problem with this reductionist approach is that exercise is very complex and hence likely to be very dirty. For example, exercise can be aerobic (oxygen) or anaerobic (lack of oxygen) and can involve resistance. Then there is intensity and duration. Is HIIT (high-intensity interval training) better than aerobic exercise? What about movement? Does exercise require you to move; is a treadmill run equivalent to an outdoor run? How important is exercise frequency; is daily better than 3-4 times a week versus the weekend warrior’s activity on Saturday and Sunday? 

The bottom line is that we know exercise works for some pwMS. However, as always we have many unanswered questions. One that Robert Motl, the doyen of exercise research in MS, raised with me in one of the coffee breaks is that we don’t know if exercise may have negative effects in certain groups of pwMS. For example, during a relapse or in more advanced MS. Is flogging a dying horse, i.e. making people with walking impairment exercise their lower limbs, potentially bad for them in that overuse of the pathway through exercise is speeding up its degeneration? We need to be careful in not making pwMS feel guilty about not exercising when we don’t have a mature evidence-base to recommend it or not.

Stubbe et al. Genetic Influences on Exercise Participation in 37,051 Twin Pairs From Seven Countries. PLoS One , 1 (1), e22 2006 Dec 20.

Background: A sedentary lifestyle remains a major threat to health in contemporary societies. To get more insight in the relative contribution of genetic and environmental influences on individual differences in exercise participation, twin samples from seven countries participating in the GenomEUtwin project were used.

Methodology: Self-reported data on leisure time exercise behavior from Australia, Denmark, Finland, Norway, The Netherlands, Sweden and United Kingdom were used to create a comparable index of exercise participation in each country (60 minutes weekly at a minimum intensity of four metabolic equivalents).

Principal findings: Modest geographical variation in exercise participation was revealed in 85,198 subjects, aged 19-40 years. Modeling of monozygotic and dizygotic twin resemblance showed that genetic effects play an important role in explaining individual differences in exercise participation in each country. Shared environmental effects played no role except for Norwegian males. Heritability of exercise participation in males and females was similar and ranged from 48% to 71% (excluding Norwegian males).

Conclusions: Genetic variation is important in individual exercise behavior and may involve genes influencing the acute mood effects of exercise, high exercise ability, high weight loss ability, and personality. This collaborative study suggests that attempts to find genes influencing exercise participation can pool exercise data across multiple countries and different instruments.

CoI: none

Pathways to Cures

Barts-MS rose-tinted-odometer ★★★★★ 

I am en route to a ‘Pathways to Cures’ meeting in Washington DC hosted by the National MS Society. The aim of the meeting is to refine the ‘Stop, Restore, and End Pathways’ for MS and to develop an international consensus on what an MS cure looks like. I am honoured to be invited to participate in this meeting and would like to thank the NMSS for inviting me. 

As always I feel like an imposter; a neurologist who dares to dream about being a public health doctor hoping to someday be in a position to say we have prevented MS, at least in a proportion of people. 

Only yesterday I read a very inspiring essay in the New England Journal of Medicine by Sonia Vallabhm who carries a rare genetic disease that at some stage of her life will strike her down and result in her dying of fatal brain disease at a relatively young age. Instead of accepting her fate her and her husband have retrained as scientists to study her disease so as to prevent its consequences. 

So many of the messages in her essay resonate with what we are trying to do in MS I, therefore, took a writer’s liberty of paraphrasing her essay from an MS perspective. Apologies about the blatant plagiarism; I hope Sonia and the NEJM will forgive me! 

If you have time please read her essay before reading my ‘fictional’ take on her messages. Sonia’s writing skills are clearly superior to mine, but the issues she raises are very clear. If you are at risk of a preventable disease that destroys the brain, why wouldn’t you want to know about being at risk of acquiring the disease in question and why wouldn’t you want to prevent the disease? 

Sonia Vallabh. The Patient-Scientist’s Mandate. N Engl J Med 2020; 382:107-109.

Eight years ago, at the age of 24, I learned that I had a 1 in 4 chance of developing multiple sclerosis. In response, I left my fledgeling career in law to retrain in biomedicine. Starting in night classes and entry-level laboratory jobs, I earned a PhD in biomedical research in the spring of 2018. I now have an established research group focused on the prevention of MS.

There is a proud tradition of activated patients driving science. Fellow travellers of this path may be familiar with the kinds of questions I fielded from day one, in particular, whether it was appropriate for patients, or potential patients, to work on their own disease. 

My goal is prevention: to preserve at-risk brains, including mine, in full health. MS is a silent disease advancing slowly: the average patient with MS is unemployed 10 years after diagnosis, in a wheelchair by 20 years and has their life expectancy clipped by about 8 years. To the best of my knowledge, there have been no prevention trials. Previous clinical trials targeting so-called prevention have focused on preventing the second clinical attack, i.e. the conversion from clinically-isolated syndrome (CIS) to clinically definite MS (second attack), have generally confirmed the known efficacy of licensed disease-modifying therapies. However, predictive or at-risk testing provides an opportunity, and arguably a mandate, to aim for a higher goal: preservation of brain function and ultimately the full quality of life. This is important as a lot of brain tissue and cognitive reserve is lost prior to the first clinical attack in MS. This is why I want to prevent developing MS. 

Because at-risk people have no clinical symptoms testing drugs as a primary prevention strategy based on an MS risk score will require testing drugs in normal people. This realization has defined my priorities for the past 5 years leading me to focus on EBV the likely cause of MS; in particular, EBV vaccination and the treatment of infectious mononucleosis. These treatment targets require a biomarker that can reflect vaccine and drug activity without a definite MS phenotype. My research programme has highlighted many other issues, for example, the need for validated tools for quantifying MS risk in the general population; appropriate recruitment infrastructure (high-risk and population-based registers); defining the presymptomatic natural history of MS; and proactive engagement with funders, public health officials and regulatory agencies. As this list suggests, redefining the aims of drug and vaccine development to encompass MS prevention leads to many new research goals and widens the relevant stakeholders we need to engage with. 

In the area of MS prevention, it will take more than a  patient-scientist partnership to drive this shift. Perhaps there is something peculiarly clarifying about defining success by honestly answering the question “What would you want for your own brain?”.

My assessment of plausibly relevant approaches was guided by my bottom line: Which approach would face the smoothest path to a first-in-human trial in healthy people at high risk of developing MS?

Guided by practicality, in 2017 we hosted a task-force to develop an MS prevention strategy (see PDF below). The potential for EBV vaccination to prevent MS was endorsed by all participants. Three years on, the building blocks of this program are advancing towards a clinical trial. The progress is slow, very slow, but we will get there. 

On the patient side, an emerging task is to rally people who are at risk of developing MS. Currently, very few of those at known risk of developing MS is seeking prevention strategies. Many are counselled against seeking this information because an unlucky result is not actionable at present. I understand this argument, but there’s more to actionability than meets the eye. To succeed in the clinic, we will need to rally supporters behind a counternarrative, one that honours the opportunity that at-risk individuals have to contribute to rewriting the collective future of people with MS. This reframing will not persuade everyone at risk, but it will resonate with some. And, especially when dealing with an uncommon disease, every person matters; every voice matters.

For me, the journey from patient to scientist continues to reaffirm that pursuing at-risk testing was the right choice for me and my family — a decision that continues to empower me in new ways as the years unfold. 

I still occasionally encounter the concern that there is a conflict of interest inherent in researching your own potential disease. But far from seeing a conflict of interest, I see an exquisite alignment of interests as I work with mentors and allies toward a trial testing a vaccine and/or drug I hope to take myself, to prevent the disease that threatens my and my families future.