Gavin Giovannoni

Stopping DMTs in advanced MS

Barts-MS rose-tinted-odometer: zero-★s

I saw her in the clinic last year for a second opinion. She has secondary progressive MS and had been on fingolimod for just shy of 4 years with an EDSS of at least 5.5. She was using a walking stick intermittently, particularly when mobilising outdoors and her EDSS was probably 6.0 or even 6.5 because on her own admission she was unable to walk 100m. She was told by her treating neurologist that according to NHS England guidelines he was going to have to stop her fingolimod because she had secondary progressive MS. He told her she must not worry because in 12 months time she could be eligible for the high-dose simvastatin or STAT-2 trial. Despite being anxious she stopped her fingolimod and two months later she had a rebound relapse with a brainstem syndrome. Repeat MRI after the relapse showed she had at least 8 new lesions. When I saw her she had an EDSS 7.0, which was during the recovery phase of her relapse. We restarted her on fingolimod. She has managed to claw back some function and her EDSS is between 6.5 and 7.0.

This case is not unique. Several times a year one of my colleagues will discuss a patient who has advanced MS (wheelchair-user) who after stopping their DMT have recurrent inflammatory activity and relapse. Please note that we have to stop DMTs when patients become wheelchair users or reach an EDSS of 7.0; this is what the NHS England’s stopping criteria mandate (black and white?).

NHS England Stopping Criteria 2019

The current DMT should be stopped if any of the following criteria are met:

1. No reduction in frequency or severity of relapses compared with the pre-treatment phase following adequate exposure to the DMTs (which varies for each DMT, but should be a minimum of 6 months)

2. Intolerable adverse effects of the drug

3. Development of inability to walk (EDSS 7.0), persistent for more than 6 months due to MS

4. Confirmed secondary progressive disease with an observable increase in disability for more than a 12 month period, in the absence of relapse activity. Secondary progressive disease would usually only be diagnosed in patients with an EDSS of 6.0 or greater. (Except for the rare phenotype of “relapsing-progressive multiple sclerosis” detailed in section 13).

Criteria 1 and 2 might lead to switching to alternative DMTs.

Criteria 3 and 4 will lead to stopping all DMTs.

Past criteria have included pregnancy, breastfeeding or attempting conception, but increasing evidence shows that some DMTs may be considered safe in these situations.

Stopping DMTs should lead to continued care within the MS team or transfer of care to services which can provide appropriate support, such as neuro-rehabilitation. If a drug is stopped for a reason other than intolerance or lack of efficacy, then it may be restarted at a later date, even though the patient may not have “requalified” through new lesions. This may apply, for instance, to people who come off a drug during pregnancy or to take an experimental drug in a trial.

Rebound MS disease activity is particularly problematic with anti-trafficking therapies such as natalizumab, fingolimod and potentially with the other newer-generation S1P modulators (siponimod, ozanimod, ponesimod). This is why I feel so uncomfortable about applying the NHS England’s stopping criteria to patients on these therapies. Another thing to remember is that the NHS England treatment guidelines are only based on evidence in terms of starting DMTs. In comparison the stopping criteria are not evidence-based, which is why I proposed we do a national trial to see how appropriate they are.

I suggested a few years ago that we, the MS community, do a randomised controlled trial to assess the efficacy of generic cladribine in patients with advanced MS. Patients having to stop their existing DMT because they have developed SPMS or reached EDSS 7.0 are randomised to treatment with generic cladribine or placebo with the primary outcome being NEDA or disease progression as defined using upper limb function. The trial will be an event driven study and if someone reaches study end-point they can be unblinded and offered a course of cladribine if they were previously treated with placebo or a further course of treatment or another off-label salvage therapy if they had been randomised to cladribine.

The SALVAGE-MS study would become part of our suite of #ThinkHand trials; i.e. to salvage upper limb function in people with more advanced MS. The real question is do we have equipoise to do this study?

Please note that in a small French study below, of stopping DMTs in pwSPMS, 35% of the cohort had relapses, or MRI activity, in the follow-up period (~5 years). Similarly, in the MS-BASE study below, of 485 DMT-stoppers vs. 854 DMT-stayers followed for at least 3-years, time to confirmed disability progression was significantly shorter among DMT stoppers than stayers. The data from these two studies would indicate that we should really question NHS England’s stopping criteria. Do you agree?

Another practice that is emerging is the stopping of DMTs in patients with so-called ‘inactive SPMS’ in the hope they become active and hence are eligible for siponimod treatment. Please note this practice puts patients like the one above at risk of rebound disease activity, which may come at a cost to the individual.

FRENCH STUDY

Bonenfant et al. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. 2016. doi: 10.1111/ene.13181

BACKGROUND AND PURPOSE: The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS.

METHODS: We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified.

RESULTS: Mean treatment duration was 60.4 ± 39.3 months, and mean follow-up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal [0.09, 95% confidence interval (CI), 0.05-0.17 and 0.07, 95% CI, 0.05-0.11, respectively], relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09-0.16). Sixteen patients experienced a relapse and 19 had a gadolinium-positive MRI scan without relapse during follow-up. A gadolinium-positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of <6 were positively associated with relapse and/or MRI activity after discontinuation (P = 0.0004 and P = 0.03, respectively).

CONCLUSION: In this retrospective study, including a limited number of patients with SPMS, the annualized relapse rate remained stable after treatment withdrawal, relative to before treatment withdrawal. Further prospective studies are needed to confirm this result and provide evidence-based guidelines for daily practice.

MS-BASE STUDY

Kister et al. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016 Oct;87(10):1133-7.

BACKGROUND: Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.

OBJECTIVES: (1) To compare time to first relapse and disability progression among ‘DMT stoppers’ and propensity-score matched ‘DMT stayers’ in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers.

METHODS: Inclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model.

RESULTS: Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period.

CONCLUSIONS: Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.

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Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Long-COVID

Barts-MS rose-tinted-odometer: ★★

If anyone who has any doubts on the debate of getting or not getting COVID-19 and taking your chances without being vaccinated needs to read the paper below in this week’s BMJ on long-COVID.

Long-COVID is a serious problem and should not be dismissed as something minor. Long-COVID is not simply post-viral fatigue. So if you are one of those people who is nervous about having the vaccine I would urge you to think again. There is no doubt in my mind getting COVID-19 is much worse and riskier than having any of the licensed COVID-19 vaccines. If you don’t have the vaccine you have to assume that at some point in the future you will get COVID-19; this virus is not going away it will become endemic.

So my message remains simple #StayCalm #BeRational #GetVaccinatedASAP

Ayoubkhani et al. Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study. BMJ 2021;372:n693

Objective: To quantify rates of organ specific dysfunction in individuals with covid-19 after discharge from hospital compared with a matched control group from the general population.

Design: Retrospective cohort study.

Setting: NHS hospitals in England.

Participants: 47 780 individuals (mean age 65, 55% men) in hospital with covid-19 and discharged alive by 31 August 2020, exactly matched to controls from a pool of about 50 million people in England for personal and clinical characteristics from 10 years of electronic health records.

Main outcome measures: Rates of hospital readmission (or any admission for controls), all cause mortality, and diagnoses of respiratory, cardiovascular, metabolic, kidney, and liver diseases until 30 September 2020. Variations in rate ratios by age, sex, and ethnicity.

Results: Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute covid-19 were readmitted (14 060 of 47 780) and more than 1 in 10 (5875) died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Rates of respiratory disease (P<0.001), diabetes (P<0.001), and cardiovascular disease (P<0.001) were also significantly raised in patients with covid-19, with 770 (95% confidence interval 758 to 783), 127 (122 to 132), and 126 (121 to 131) diagnoses per 1000 person years, respectively. Rate ratios were greater for individuals aged less than 70 than for those aged 70 or older, and in ethnic minority groups compared with the white population, with the largest differences seen for respiratory disease (10.5 (95% confidence interval 9.7 to 11.4) for age less than 70 years v 4.6 (4.3 to 4.8) for age ≥70, and 11.4 (9.8 to 13.3) for non-white v 5.2 (5.0 to 5.5) for white individuals).

Conclusions: Individuals discharged from hospital after covid-19 had increased rates of multiorgan dysfunction compared with the expected risk in the general population. The increase in risk was not confined to the elderly and was not uniform across ethnicities. The diagnosis, treatment, and prevention of post-covid syndrome requires integrated rather than organ or disease specific approaches, and urgent research is needed to establish the risk factors.

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COVID-19 vaccine thrombosis update

Barts-MS rose-tinted-odometer: ★★

Last week I heard from an Italian colleague that in Italy when many people arrive for the COVID-19 vaccine slot and find out that the vaccine on offer is the Oxford-AstraZenca (AZ) vaccine they say no thank you and leave. The main reason they give for turning down the AZ vaccine is the thrombosis risk. I wonder if these people are aware of the new data that emerged last week (see below).

In this big data study from the US, the incidence of cerebral venous thrombosis (CVT) after COVID-19 diagnosis was 39.0 cases per million people who get COVID-19. This was higher than the CVT incidence after influenza (0.0 per million people or adjusted relative risk = 6.7) or after receiving the Pfizer-BionTech or Moderna RNA vaccines (4.1 per million people, adjusted relative risk = 6.4 higher).

The bottom line is COVID-19 is way riskier than the COVID-vaccines in causing thrombus and contrary to a common belief the risk is not only restricted to the AZ or J&J vaccines, which use adenoviral vectors but with the COVID-19 mRNA vaccines well. This suggests it may be the immune response to the SARS-CoV-2 spike protein that induces cross-reactivity and sets up a very rare thrombotic state.

It is never easy to explain risks and relative risks, but the following infographic doing the rounds on social media may help. What do you think?

Please #StayCalm and #GetVaccinatedASAP.

Taquet et al. Cerebral venous thrombosis: a retrospective cohort study of 513,284 confirmed COVID-19 cases and a comparison with 489,871 people receiving a COVID-19 mRNA vaccine. OSF 15-April-2021.

Using an electronic health records network we estimated the absolute incidence of cerebral venous thrombosis (CVT) in the two weeks following COVID-19 diagnosis (N=513,284), or influenza (N=172,742), or receipt of the BNT162b2 or mRNA-1273 COVID-19 vaccines (N=489,871). The incidence of portal vein thrombosis (PVT) was also assessed in these groups, as well as the baseline CVT incidence over a two-week period. The incidence of CVT after COVID-19 diagnosis was 39.0 per million people (95% CI, 25.2–60.2). This was higher than the CVT incidence after influenza (0.0 per million people, 95% CI 0.0–22.2, adjusted RR=6.73, P=.003) or after receiving BNT162b2 or mRNA1273 vaccine (4.1 per million people, 95% CI 1.1–14.9, adjusted RR=6.36, P<.001). The relative risks were similar if a broader definition of CVT was used. For PVT, the incidence was 436.4 per million people (382.9-497.4) after COVID-19, 98.4 (61.4-157.6) after influenza, and 44.9 (29.7-68.0) after BNT162b2 or mRNA-1273. The incidence of CVT following COVID-19 was higher than the incidence observed across the entire health records network (0.41 per million people over any 2-week period). Laboratory test results, available in a subset of the COVID-19 patients, provide preliminary evidence suggestive of raised D-dimer, lowered fibrinogen, and an increased rate of thrombocytopenia in the CVT and PVT groups. Mortality was 20% and 18.8% respectively. These data show that the incidence of CVT is significantly increased after COVID-19, and greater than that observed with BNT162b2 and mRNA-1273 COVID-19 vaccines. The risk of CVT following COVID-19 is also higher than the latest estimate from the European Medicines Agency for the incidence associated with ChAdOx1 nCoV-19 vaccine (5.0 per million people, 95% CI 4.3–5.8). Although requiring replication and corroboration, the present data highlight the risk of serious thrombotic events in COVID-19, and can help contextualize the risks and benefits of vaccination in this regard

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Stay calm and get vaccinated

Barts-MS rose-tinted-odometer: ★★★

We can speculate until the cows come home, but speculation remains guesswork. Until a similar study to the one below on T-cell responses to the COVID-19 vaccine is done in people with MS on different DMTs we can’t be confident that people who don’t seroconvert after the vaccine have adequate or protective anti-SARS-CoV2 spike protein T-cell responses.

However, my message remains the same around vaccinations. The COVID-19 vaccines are safe and we don’t have any reason to suspect the vaccines have any effect on your MS in the long term. Apart from transient worsening of symptoms, which are reversible, in response to the flu-like symptoms from the vaccine pwMS seem to be tolerating the vaccine without any problems. The latter is more common in patients with advanced disability and can be managed with prophylactic paracetamol and/or ibuprofen.

Good things come to communities who are patient. My advice would be to stay calm and #GetVaccinatedASAP.

Painter et al. Rapid induction of antigen-specific CD4+ T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination. bioRxiv 2021 doi: https://doi.org/10.1101/2021.04.21.440862

The SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses in healthy individuals following mRNA vaccination. Vaccination induced rapid near-maximal antigen-specific CD4+ T cell responses in all subjects after the first vaccine dose. CD8+ T cell responses developed gradually after the first and second dose and were variable. Vaccine-induced T cells had central memory characteristics and included both Tfh and Th1 subsets, similar to natural infection. Th1 and Tfh responses following the first dose predicted post-boost CD8+ T cell and neutralizing antibody levels, respectively. Integrated analysis of 26 antigen-specific T cell and humoral responses revealed coordinated features of the immune response to vaccination. Lastly, whereas booster vaccination improved CD4+ and CD8+ T cell responses in SARS-CoV-2 naive subjects, the second vaccine dose had little effect on T cell responses in SARS-CoV-2 recovered individuals. Thus, longitudinal analysis revealed robust T cell responses to mRNA vaccination and highlighted early induction of antigen-specific CD4+ T cells.

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#MSCOVID19: Cladribine 3 vs. Ocrelizumab 1 vs. Fingolimod 0

Barts-MS rose-tinted-odometer: ★★★★★

Finally, the early Israeli COVID-19 vaccine seroconversion rates are out as a peer-reviewed publication. This data is not new but comes with being vetted by the scientific community and hence can be quoted and discussed at scientific meetings.

Protective humoral immunity was 97.9% in healthy subjects, 100% untreated pwMS, 100% in cladribine-treated pwMS, 22.7% in ocrelizumab-treated pwMS and 3.8% in fingolimod-treated pwMS. As I have said before this is only half the story and we need to know what happens on the T-cell side.

IgG antibodies to the virus implies a good T-cell response as well; this is because to class switching to IgG happens in the germinal centres with T-cell help. The corollary does not necessarily hold, i.e. if you don’t make IgG antibodies you can’t assume that vaccine-induced T-cell responses are absent. This is why I predict, based on the fact that both ocrelizumab and fingolimod treated pwMS recover from COVID-19 implying their T-cells are working and helping to clear the virus, that both ocrelizumab- and fingolimod-treated patients are likely to have some T-cell immunity to SARS-CoV-2 spike protein post-vaccination.

Please note this is a prediction and we will need to wait for more detailed immunological studies. Even if patients on these agents have some T-cell responses the question will remain whether this blunted vaccine-induced immunity against SARS-CoV-2 will be sufficient to protect these patients against getting COVID-19 or repeated episodes of COVID-19? This question will take much longer to answer, but I suspect this limited immunity won’t be sufficient because vaccine immunity is likely to wane with time and new immune escape variants of SARS-CoV2 will emerge. Already public health officials are planning for rounds of booster vaccines to cover new variants. What this means is that vaccine-readiness will become uppermost in the minds of pwMS and HCPs when deciding on which DMTs to choose for particular patients.

The good news is that if you have MS and have been treated with cladribine there is no blunting of vaccine-induced responses. This is not surprising and was predicted based on the immunology of cladribine and justifies my previous blog post taking the NMSS to task on their ill thought out initial COVID-19 vaccine guidelines. Fortunately, these have been updated and pwMS on cladribine can be confident to go ahead with getting vaccinated ASAP.

Figures from Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

I would extrapolate the ocrelizumab vaccine data to the other anti-CD20 therapies, i.e. rituximab, ofatumumab and ublituximab, but not necessarily the fingolimod data to the other S1P modulators. There is evidence that fingolimod not only traps lymphocytes in lymph nodes but also depletes lymphocytes. In comparison to fingolimod, ozanimod and ponesimod deplete lymphocytes less intensely and at least for ponesimod, the recovery of lymphocytes is very rapid implying lymphocytes are not depleted on this drug. So I would not be surprised if ponesimod, and possibly ozanimod, have less of an effect on vaccine responses than fingolimod. As for siponimod, I predict it will be closer to fingolimod in terms of its effect on neoantigen (new antigen) vaccine responses such as the COVID-19 vaccines.

Does this data change anything about my current practice? No, not really, it is entirely in keeping with what I predicted. My advice is still #GetVaccinatedASAP. This data however may impact what treatment patients with MS decide to start off on; if vaccine responses are important to you, say for travel and/or work reasons, you may want to avoid S1P modulators and anti-CD20 therapies.

Please note I have put on my rose-tinted glasses; the sun is shining outside and spring is wonderful 😉

Achiron et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

Background and Aims: The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs.

Methods: We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated.

Results: Protective humoral immunity of 97.9%, 100%, 100%, 22.7%, and 3.8%, was observed in COVID-19 vaccinated healthy subjects (N = 47), untreated MS patients (N = 32), and MS patients treated with cladribine (N = 23), ocrelizumab (N = 44), and fingolimod (N = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5–55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination.

Conclusions: Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.

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How flipped is your consultant?

Barts-MS rose-tinted-odometer: ★★

If you don’t measure it you can’t change it. The fact that the UK was performing so poorly relative to other EU countries on the EMSP’s MS barometer was one of the reasons why I got into MS politics and helped put together the ‘Brain Health: Time Matters’ policy document.

In 2015, despite being the second wealthiest nation in Europe, the UK was in the bottom three of the EU league table in terms of prescribing DMTs, particularly high efficacy DMTs. Fortunately, things have improved slightly and we are now mid-table, but way below average (see figure below). Is this good enough? NO! The under-treatment of MS in the UK will obviously be linked to poorer outcomes, i.e. more disabled, more unemployed, more demented and smaller-brained people living with MS in the UK compared to comparator countries above us in the league table.

I am often asked if I had MS what country would I want to live in to have my MS treated. I rarely hesitate, it has to be either Sweden or Australia. Why? Because these two countries have universal healthcare policies and they both allow their MSologists to manage MS how they see fit. This is why both Sweden and Australia have about 70% of their patients on high efficacy DMTs. There are also no Swedish or Australian DMT police standing over their consultants saying you can only use drug X or refer this patient for HSCT if they fulfil these criteria. Yes, the Swedish and Australian healthcare systems trust their consultants to get on with the job they have been trained to do, i.e. to treat MS with very little central interference.

Some conservative neurologists argue that both Sweden and Australia are over-treating MS and by doing so they are exposing people who will eventually turn out to have benign MS to unnecessary risks associated with high-efficacy DMTs. Please remember that only a small minority of people with MS turn out to have benign MS. Therefore the non-Swedish-Australian or conservative approach to treating MS puts the majority of pwMS at risk of under-treating their disease to protect the minority. This could be referred to as the anti-vaxxer approach to treating MS; let’s not treat MS aggressively so that we harm nobody.

In comparison, the Swedes and Australians will be exposing a small proportion of their benign MS patients to unnecessary risks to offer the majority the protection their brains need from under-treated MS. This is like the public health approach to vaccines; let’s treat MS aggressively to improve the outcome of the majority and by doing this we are prepared to accept some collateral damage in terms of adverse events.

Another argument that is often used against the active-treatment approach of the Swedes and Australians is that if everyone ends up on high efficacy therapy what do you do next? I counter this argument by saying these patients are probably on high-efficacy treatment because they need to be on high-efficacy treatment.

The other issue that needs discussion is the variation within countries and even within MS centres. When I first saw the DMT prescribing data from Blueteq, the NHS high-cost drug database, I was appalled. There is such wide variation between UK centres in terms of DMT prescribing behaviour that even NHS England are concerned. It can’t be right that some MS centres have 80% of their patients on high-efficacy DMTs and other centres have less than 20% of their patients on these treatments.

Some UK centres don’t prescribe some classes of DMT. In fact, the latter may be illegal. There is in fact an act of parliament stating that NHS centres have to offer NICE approved therapies. Therefore refusing to offer and treat someone who is eligible for say alemtuzumab could be legally challenged. As a result of this variation, we started the Raising-the-Bar initiative to address variation in MS service provision across the UK. A national audit is the keystone of this initiative and all MS centres will be able to see how they are performing relative to the national average and other regional centres. Hopefully, this national audit data will act as the catalyst to stop the scourge of undertreated MS in the UK.

The audit data will be so granular that it has the potential to expose outliers at the individual consultant level. For example, if one consultant has no patients treated with alemtuzumab, cladribine or HSCT and his/her colleagues in the same centre has substantial patients on these treatments it may trigger a review of that consultant’s fitness to practice as an MSologist. I am sure many neurologists will be appalled by this suggestion, but this type of individual performance review is widely used in surgical specialities and will arrive in neurology soon. In fact, it already has in some countries. If you are an epilepsy expert and are not referring a certain proportion of your patients for epilepsy surgery every year then you will have your fitness to practice as an epilepsy expert questioned. Epileptologists have agreed that a small number of patients with drug-resistant epilepsy will benefit from surgery and if one of their colleagues is not identifying and referring these patients for surgery then they are not practising according to international standards.

My dream is that every MS centre in the UK will not only have access to their audit data for quality and performance review but patients will be able to access this data on a publically available website so that that can ascertain how conservative or active their MS centre is at treating MS. My vision is to have an MS-Advisor app modelled on TripAdvisor that will allow patients to review and provide feedback on their MS service. There is nothing like a bad review to change behaviour.

So if you have MS and think your disease is being under-treated you should ask your HCP for their audit figures, i.e. how many of their patients are on DMTs, how many are on high efficacy DMTs and how do their figures compare to their colleagues and to the national average. If they are not prepared to provide you with this data you can always put in a freedom of information request.

Yes, the Raising-the-Bar national audit is going to make it hard for participating centres to not participate in the audit and to ignore their own audit data. The objectives of the RtB initiative is to raise the standard of MS services for pwMS, to reduce the under-treatment of MS and to ultimately improve MS outcomes and the quality of life of our NHS patients.

So when I ask has your neurologist flipped; I mean has your neurologist adopted a more active approach to treating MS. Are they flipping the pyramid?

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Two, four, six, eight, who do you appreciate?

Barts-MS rose-tinted-odometer: ★

This week I was asked by two patients independently of each other who had delayed access to treatment if this could explain why they now have secondary progressive MS. In parallel, I had a meeting with a friend yesterday, who was the primary driver of the 21-year interferon-beta follow-up survival study (see below), who said that to him this was the most convincing data to support the early treatment paradigm in MS.

In summary, trial subjects in the pivotal original interferon-beta-1b study who had delayed access to interferon-beta-1b because they were randomised to receive placebo were 50% less likely to be alive at 21 years compared to study subjects with early access to treatment. Was this due to the impact of interferon-beta on MS or some other confounding factor? In the 69 pwMS for whom information on the relationship of death to MS was available 78% were judged to have died from MS-related complications. This tells us that IFN-beta increases your life expectancy by reducing MS-related complications that can cause death in the future. The latter include swallowing problems that are associated with aspiration pneumonia, urinary dysfunction that lead to urinary tract infections and septicaemia, immobility and pressure sores, falls and fractures, to name the most common causes of premature death in pwMS.

You need to remember that this was a placebo-controlled study and the subjects on placebo were switched to active treatment after 3 years, with some subjects having to wait up to 5 years (trial recruitment was from June 1988 to May 1990; with placebo-treated subjects given free commercial supply as of October 1993). What this study shows is that delaying access to treatment by just 3-5 years has a major impact on long-term outcomes.

Please note that apart from suicide most pwMS get to EDSS 10 or death as a result of MS by passing through EDSS stages 2, 4, 6 (stick), 8 (wheelchair/bed). So my answer to these patients was yes your delayed access to DMTs in the early 2000s is almost certainly the reason why you now have secondary progressive MS and are disabled.

Please note this there is now overwhelming evidence from other controlled trials and real-life data to support the interferon-beta 21-year mortality data. In fact, the debate about early treatment and MS outcomes is so widely accepted that it has now has shifted from early access to DMTs to early access to highly effective DMTs, i.e. flipping the pyramid. It is clear that pwMS who are treated with more effective DMTs first-line do so much better than those who are asked to wait (watchful waiting) or are escalated gradually up the DMT ladder (slow escalation). This is why, despite us designing the early treat-2-target NEDA trial, our centre couldn’t participate in the trial comparing maintenance-escalation vs. flipping the pyramid. We simply don’t have equipoise; in other words, we don’t think it is ethical to randomise patients to a treatment arm that is less effective and hence will result in poorer long-term outcomes and probably poorer long-term survival. This is why it is our current clinical practice to offer pwMS who have active disease and are eligible under the NHSE algorithm for treatment access to highly effective treatment first-line.

We are so convinced about the early treatment that we are doing the ATTACK-MS trial, which will explore if access to the highly effective treatment natalizumab, 2 months earlier than what happens in routine practice, improves outcomes. Yes, we will be randomising patients before they have finished the MS diagnostic pathway to treatment vs. delayed access, i.e. only 2 months later when they have a definitive diagnosis of MS. We anticipate that the ATTACK-MS study will activate the MS community to treat the MS brain as we treat the brain in stroke. Forget about years, every day, week or month for the untreated MS brain is like every second, minute or hour in the non-perfused brain of a person having a stroke.

Yes, in MS time really is brain and by delaying access to DMTs and potentially highly effective DMTs is unacceptable in the modern era of treating MS. The data below not only supports the maxim “Time is Brain” but “Time is Life“, why would anyone wait to treat someone with active MS knowing this?

Figure from Neurology 2012;78(17):1315-22.

Goodin et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology. 2012 Apr 24;78(17):1315-22.

Objective: To examine the effects of interferon beta (IFNβ)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments.

Methods: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNβ-1b 250 μg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary.

Results: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNβ-1b 250 μg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNβ-1b 250 μg-treated patients (46.0% among IFNβ-1b 50 μg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect.

Conclusions: There was a significant survival advantage in this cohort of patients receiving early IFNβ-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNβ-1b benefit on all-cause mortality.

Classification of evidence: This study provides Class III evidence that early treatment with IFNβ-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

Goodin et al. Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNβ-1b study. BMJ Open. 2012 Nov 30;2(6).

Objectives: Compared with controls, multiple sclerosis (MS) patients die, on average, 7–14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon β-1b, mortality was reduced by 46–47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts.

Design: Long-term follow-up (LTF) of the pivotal RCT of interferon β-1b.

Setting: Eleven North American MS-centres participated.

Participants: In the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment.

Interventions: Using multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients.

Primary outcome: An independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships.

Results: Among the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths.

Conclusions: In this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.

If you are interested you can watch my presentation from last year’s ACTRIMS-ECTRIMS meeting during which I make the case for flipping the pyramid. Please note the ATTACK-MS study paradigm takes this concept of time is brain even further. Do you agree with this approach?

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An existential crisis

Barts-MS rose-tinted-odometer: zero-★s

The Barts-MS blog is having yet another existential crisis.

Have you been to Speakers’ Corner on the Northeast point of Hyde Park in London? If you haven’t I would recommend visiting and spending an hour or so watching and listening. Speakers’ Corner is where anyone, who is anyone, can stand on a soapbox and speak their mind on any topic that takes their fancy. A Victorian version of the modern podcast, but only live. Another example of an early form of social media was pamphleting. The so-called pamphleting wars started in the 1600s shortly after the printing press. Individuals and Societies used pamphleting as a means of getting their message to people on the streets. Popular pamphleteers, dare I say early influencers, were Daniel Defoe, Thomas Hobbes, Jonathan Swift, John Milton, and Samuel Pepys.

Orator at Speakers’ Corner in London, 1974. (Image from Wikipedia)

I came across pamphleting when I was preparing my talk for James Parkinson’s memorial day and discovered that Parkinson used pamphleting as means to run political campaigns. Interestingly, Parkinson wrote under the pseudonym, ‘Old Hubert’, and was a prominent member of two campaigning societies for reforms at the time: the London Corresponding Society and the Society for Constitutional Information.

Another pamphleting example I discovered whilst researching diet was by William Banting, a portly Victorian gentleman, who discovered by deductive reasoning and trial and error that a low-carbohydrate-high-fat diet led to rapid and sustained weight loss. Instead of writing a book, he wrote a pamphlet and the LCHF diet is now eponymously referred to as the Banting Diet and the practice of being on his diet as ‘banting’. Tilly Tansy, a medical historian and colleague, refers to pamphleting as being the equivalent of Twitter in the pre-digital era.

I wonder what Georgian and Victorian Londoners would have thought about YouTube and vlogging, a very modern version of the Speakers’ Corner, and the new generation of influencers it has spawned? Surely they are the modern equivalents of James Parkinson and William Banting, except with more rapid global appeal.

What all social media platforms have in common is that they allow almost everyone a platform, be it writing (Twitter, WordPress, Blogger), pictures (Instagram, Pinterest), voice (podcasting), music (Soundcloud) or video (YouTube vlogging), to compete with each other and sometimes head-on with the traditional media.

I argue that social media is the ultimate expression of a mature democracy, which is why as a liberal I am extremely concerned about the mounting level of political interference in social media and the governance of the web. Censorship and loss of net neutrality are existential threats and should be resisted. This has come to the fore during the US 2020 Presidential election and more recently with the backlash against the anti-Vaxxers.

A few years ago I was referred to at a public meeting as being an MS influencer. A modern term to describe someone who uses social media to influence the people who follow them. What makes one person become an influencer and stand out from the crowd is no different from a speaker on Speakers’ Corner who draws the biggest crowd. The most important characteristics are reputation, i.e. being trustworthy or honest, having standards and sticking to them, and being consistent. Another characteristic is novelty; being prepared to put your head above the parapet and not follow the crowds. You need to have something new to say or at least have a new spin on an old idea. The problem with this blog is that sometimes what one blogger writes is assumed to represent the opinions of the other bloggers on the site and the Barts-MS collective. This is clearly not the case and explains why we often disagree with each other. Do I really have to remind this audience that debate is healthy and that calling each other out over a bad idea is how science works?

Very few ideas are original, but how you communicate them is key to novelty and stickiness. Stickiness is an adjective to describe how well ideas stick and are transmitted in society. Less is usually more when it comes to social media. Addressing an unmet need is also critically important. The unmet need, however, is in the eye of the beholder. You can’t please everyone so you need to define your audience and be careful not to stray off target. The real power of social media is its ability to segment the world; what is important to one person may be irrelevant to another. Having a narrative is another important component of successful social media influencers. In a world where eyeballs mean everything having a compelling story to tell often makes the difference. My daughters who are both digital natives only follow people who have a narrative.

From a personal perspective, an important part of using social media includes forced self-reflection and using it as a form of documentation; a modern version of a diary. By using social media to think aloud and develop my thoughts with feedback from my colleagues and followers allows me to be less rigid in my thinking, think more laterally and be more accommodating of other people’s ideas. Having a sounding board and a collective of thinkers can only help with the adoption of ideas and the impact they have on the wider world.

I am acutely aware that there are many critics of social media platforms and the new generation of influencers these platforms are producing, but this is usually out of ignorance of the historical role social media has played in society. Be it the speakers on Speakers’ Corner, the Pamphleteers on the streets of Georgian, London, or us Bloggers of today we are the underpinnings of an old and threatened political movement called liberalism.

Social media is a genre that should be championed and protected from the rising wave of populism and autocracy. There is currently a larger debate on whether or not social media platforms should be responsible for their content or are just providers of a platform for free speech. Shortly after the US elections, Donald Trump’s account was suspended on Twitter and Facebook and Parler, the alt-tech microblogging and social networking service, was taken down by Amazon and its app was removed from both Apple’s and Google’s app stores. Parler was being used by Donald Trump supporters, conservatives, conspiracy theorists, and far-right extremists. It is clear that correcting, then deleting and apologizing for offending content is not sufficient; critics want a mechanism in place to prevent the content from being posted in the first place. Apple has only just allowed Parler’s app back onto Apple’s store. “In a letter to two Republican lawmakers on Monday, Apple said Parler had made updates to its app and content moderation policy that would lead to it being reinstated”, BBC 6-April-2021.

Over the year’s this site has had its fair share of complaints. As it is not an official website of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust who is responsible for its content? Apart from several of us moderating comments from readers the actual posts of the individual bloggers, such as this one, are not edited or moderated by an editor. The content is the responsibility of the individual writers (see disclaimer below). Despite this and as a result of a recent complaint we, Barts-MS, are being asked to take responsibility for the blog’s content. Unfortunately, we don’t have the resources or the time to moderate each blog post.

The analogy of this blog being a modern soapbox and the speakers using the soapbox having to take responsibility for their own words is not going to wash with our critics. So we have a dilemma. Do we make the blog an official publication with a board of editors who then take responsibility for its content? This will make the content boring and turgid. Do we censor and/or ban individual bloggers? This will upset their loyal followers. Do we close down the blog and let each writer go their separate ways? This will at least do away with the need for collective action. Any advice would be much appreciated.

This is not the first time this blog has had an existential crisis, however, it may be its last time.

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Please note the content of this post is based on ‘Influencers’ a piece published by Professor Gavin Giovannoni on Medium on 18-March-2019.

#MSCOVID19: T-cell response on ocrelizumab

Barts-MS rose-tinted-odometer: ★★★★★

As you know the vast majority of pwMS on anti-CD20 therapy who get COVID-19 or for that matter any other viral infection recover. In other words, their immune systems work despite blunted or absent B-cell or antibody responses. This study presented yesterday at the AAN meeting confirms that ocrelizumab-treated patients who get COVID-19 have good robust T-cell responses. Almost all of these patients also had antibody responses to the virus. The ocrelizumab-treated cases that fail to seroconvert may therefore represent a publication bias. However, as this study doesn’t include the 5% of subjects on ocrelizumab who succumb to COVID-19 we can’t assume this applies to all ocrelizumabers.

It will be interesting to see these results replicated with the COVID-19 vaccines. Although wild-type infection with SARS-CoV-2 is likely to provide a more robust immunological challenge than a COVID-19 vaccine, I can’t see why the vaccine won’t induce T-cell responses as well. The question will be how few patients fail to respond to the vaccine at both an antibody and T-cell level.

I am sure a large number of ocrelizumabers or anti-CD20ers and their HCPs will be relieved to see these results (or not).

Kister et al. Preliminary Results of Ongoing, Prospective Study of Antibody and T-Cell Responses to SARS-CoV-2 in Patients With MS on Ocrelizumab or Other Disease-Modifying Therapies. AAN 2021

Objective: 1. To assess SARS-CoV-2 seropositivity in 1,000 patients with multiple sclerosis (MS) and its association with demographic and disease-related characteristics, and disease-modifying therapy (DMT); 2. To evaluate the persistence of antibody and T-cell responses in a subset of these patients who were receiving ocrelizumab (OCR), other DMT or no DMT at the time of COVID-19 infection. Background: Since March 2020, ˜15% of patients attending NYU MS Care Center (NYUMSCC) in New York City had COVID-19. It is unknown whether DMTs affect the persistence of antibody and T-cell responses to SARS-CoV-2.

Design/Methods: Patients from NYUMSCC were invited to undergo serologic assessment using Elecsys Anti-SARS-CoV-2 (Roche Diagnostics) and multiplex bead-based immunoassays of antibody responses to SARS-CoV-2 nucleocapsid and spike proteins. A subset of patients with or without COVID-19 history underwent a study of T-cell responses to SARS-CoV-2 spike protein using IFN-? enzyme-linked immunosorbent spot (Invitrogen) and TruCulture (Myriad RBM) spike protein assays and live virus immunofluorescence-based microneutralization assay.

Results: Since January 2021, 100 unvaccinated patients with MS were enrolled (mean 41 years; 63% female; 45% non-white; 35% on OCR; 26% had COVID-19). Antibody and T-cell results were available for 40 patients (26 on OCR; 17 had COVID-19, median 10 months before sampling). Of the 40, Elecsys Anti- SARS-CoV-2 assay identified all but 2 COVID-19+ patients, and multiplex bead-based assay identified all but 1 COVID-19+ patient as seropositive. Neither assay had false positives. T-cell activation based on induced IFN-gamma secretion was observed in 10/17 COVID-19+ patients and 1 patient without COVID-19 history who developed PCR-confirmed COVID-19 five days after sampling. Anti-SARS-CoV-2 antibody response was detected in 4/5 and T-cell response in 3/5 OCR-treated COVID-19+ patients.

Conclusions: Preliminary results suggest persistent humoral and T-cell immune memory to SARS-CoV-2 up to 10 months following infection even in B-cell depleted patients with MS. Updated results will be presented.

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Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

The Star-MS trial: to be HSCTed or not

Barts-MS rose-tinted-odometer: ★★★

There is little doubt in my mind that HSCT is the most effective DMT we have for treating MS. The latter is based on NEDA (no evident disease activity) rates post-HSCT and brain volume loss data after year one. HSCT appears to put the majority of treated patients into long-term remission and normalises end-organ damage as measured by brain volume loss. In addition, a not insignificant proportion of HSCT-treated patients may be cured depending on how you want to define an MS cure. Despite these data most MSologists however, consider HSCT too risky to refer patients for treatment and hence prefer to go with the more acceptable risk profile of licensed DMTs. This is why HSCT hasn’t taken off as a mainstream treatment for MS and remains a niche treatment.

What is not known is that HSCT may yet prove to be one of the most cost-effective DMTs we have. Although quite expensive, with most of the costs front-loaded, HSCT does lead to significant cost savings in the long-term (see study below). I wonder if healthcare systems will clock this and take the bold step of underwriting more HSCT treatments for MS with the promise of long term cost savings? The problem we have in medicine is that healthcare budgets typically run on an annual cycle and so costs savings unless made the same year often don’t influence treatment decisions.

“Why should I spend more money today to only save money in the 5 years time? My responsibility is to this year’s or maybe next year’s budget not the budget in 5 years time.”

The counter-argument to this is should be if I don’t save my brain volume this year or next year, by the time I get to year 5 in my disease course it will be too late. At the moment MS brain and spinal cord damage are irreversible. Yes, time really is brain.

What do you do as a person with MS who has decided to be treated with HSCT, but your neurologist says no? Do you find a neurologist who will say yes? Do you travel abroad and take the private route? Or do you accept your neurologist’s advice and go for the safer, but ultimately more expensive, licensed but less effective DMT?

The good news is that we in the UK will soon be starting the StartMS trial, which will compare autologous stem cell transplantation (AHSCT) versus alemtuzumab or ocrelizumab in relapsing-remitting MS. This means at least some of you will be offered the opportunity to be randomised to AHSCT or ocrelizumab/alemtuzumab. A major outcome of this study will be a cost-comparison to see how much money it will save the NHS. Exciting or not? Some people are arguing that we don’t need this study as the information is already available. Not sure I agree. Sometimes doing your own research and generating your own data is what is required to change behaviour, i.e. the wide adoption of HSCT as a treatment for MS.

Orlewska et al. Impact of Immunoablation and Autologous Hematopoietic Stem Cell Transplantation (AHSCT) on Treatment Cost of Multiple Sclerosis: Real-World Nationwide Study. Value Health Reg Issues. 2021 Apr 14;25:104-107.

Objectives: To provide real-world data on the impact of autologous hematopoietic stem cell transplantation (AHSCT) on treatment costs of patients with multiple sclerosis (MS) in Poland.

Methods: Medical data of 105 patients who underwent AHSCT in the years 2011 to 2016 were obtained from the National Health Fund (NHF) database. Treatment costs were calculated from the public payer’s perspective per patient-year for the total available period as well as 12 months before and after AHSCT. The statistical analysis was performed using MATLAB 2016b.

Results: Mean treatment-related costs covered by the NHF per patient-year before and after the transplantation were €4314.9 and €1188.8 , respectively. The average cost of disease-modifying drugs per patient was reduced from €2497.9/year before to €65.3/year after AHSCT.

Conclusions: Although the initial cost of AHSCT is high, the costs involving AHSCT and post-AHSCT treatment could, according to our analysis, pay off in 3.9 years, when compared to the costs of disease-modifying drug therapy in aggressive MS. The study provides evidence that the AHSCT can lead to significant savings in treatment costs of aggressive MS from the public payer’s perspective.

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