How environmentally friendly is your DMT?

Barts-MS rose-tinted-odometer: ★★★★★
COP26 Land Green & Ocean Blue  #37328c #8cdc73

Did you know that the world will use between 8 billion and 10 billion syringes for COVID-19 vaccinations alone? Apart from this, the world uses approximately 16 billion syringes per year. Over half of these are used outside of the health care system each year by individuals with diabetes, migraines, allergies, infertility, arthritis, HIV, hepatitis, multiple sclerosis, osteoporosis, psoriasis, or other conditions. 

With COP26 top of mind do you ever consider the environmental impact of your DMT? I have simply assumed that because they are medicines and prescribed for a serious disease the environmental impact is justified. Could the environmental impact of injectable or intravenous therapies be another reason to embrace oral treatments? Or is the environmental impact related to the manufacturing process of oral treatments greater? 

Is this something that you would consider to be an important factor when making a decision about which DMT to choose? For example, would a lower environmental impact of a 6-monthly ocrelizumab infusion be a factor in choosing it over a monthly subcutaneous injection of ofatumumab?  After all, both of these DMTs are anti-CD20. Would you not want to choose the one with the lowest environmental impact?

Some of you may already be aware of our ClinicSpeak DMT decision aid we run to help pwMS make decisions about which DMT to start. Do you think we should include the environmental impact of the various DMTs on the list of factors to consider when making a decision?

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

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 and are not meant to be interpreted as personal clinical advice. 

EBV: is it time to pluck the black swan?

Barts-MS rose-tinted-odometer: ★★★★★
London Gray & Raining #666677 #C4D3DF

SEPSEPIEN a commentator this morning said: “Would have been more rewarding to find a DMT that successfully addresses the causes of MS”. I agree and I really think we have found the cause of MS. It is Epstein Bar Virus (EBV). The epidemiology is pretty convincing that EBV acts in the MS causal pathway and all of our effective i.e. licensed DMTs work on memory B-cell where the latent EBV virus resides. 

The piece on my #1 ECTRIMS-2021 highlight, i.e. the MRI changes in relation to treatment with Atara Bio’s anti-EBNA1 allogeneic CTLs (cytotoxic T-cells), has resulted in at least ten emails from business analysts wanting to speak to me about the product. I think it is my reference to a ‘Black Swan’ that piqued their interest. What they don’t realise is that when you pluck a black swan it looks just like a plucked white swan.

So if Atara Bio gets their product to market they will get pipped by the simple repositioning of the licensed DMTs as anti-EBV agents. What do I mean? 

Rituximab (anti-CD20) is licensed to treat EBV-associated lymphoproliferative disorders. Peripheral EBV viral loads plummet when you administer anti-CD20 therapies. In other words, anti-CD20 therapies are anti-EBV drugs so why would you need to use an expensive cellular therapy? To get into the CNS. Step up the CNS penetrant BTK inhibitors.

Ibrutinib the first licensed BTKi is a potent anti-EBV drug and works very well against EBV-associated lymphomas including CNS lymphomas. EBV in fact uses BTK as a signalling molecule to bypass B-cell receptor-mediated cell cervical signals.  

MD produced a wonderful and very influential review showing all of our DMTs in MS work via memory B-cell reducing their levels in the periphery with the exception of natalizumab that blocks trafficking of memory B-cells into the CNS. 

So all it will take for Big Pharma to pluck Atara Bios black swan is for them to produce data showing how their DMTs impact EBV viral infection in the periphery and potentially in the CNS. The frustrating thing for me is I have been trying to get Pharma to do these studies for decades. Just maybe with a black swan soaring up above they may start to listen. I suspect some of the companies have data on this already.

The good thing that Atara Bio has done is to move EBV centre stage. So maybe now we will get some momentum behind our EBV vaccination study off the ground. 

For those of you who have progressive MS please note how much improvement occurred in the study subject in the Atara Bio phase 1 study. It is almost too good to be true, which is why I referred to it as the Lazarus effect

A plucked swan; was it a black or white swan?

Baker et al. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017 Feb;16:41-50. 

Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19+, CD27+ memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

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 and are not meant to be interpreted as personal clinical advice. 

Do you have progressive MS; is your MS salvageable?

Barts-MS rose-tinted-odometer: ★★★★★
Another Jazzy Blues Saturday #163780 (VW’s code)

As you are aware Professor Alan Thompson was awarded the Charcot prize from ECTRIMS this year. The award recognised his long and illustrious career in the field of MS and in particular his contribution to the study of progressive MS.  However, Professor Thompson’s final message in his Charcot Lecture  – Progressive multiple sclerosis – a personal perspective – ‘that once you have clinically manifest progressive MS with disability the therapeutic window has probably shut’ has had some blowback on social media. 

His final message may dampen the spirits of many of you living with progressive MS and challenges some of the research we are involved in. 

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I was personally disappointed that he did not mention Kurtzke’s length-dependent axonopathy hypothesis and the rationale for multiple therapeutic windows in MS, which we recently resurrected as a concept. It is because MS is a central length-dependent axonopathy that we have therapeutic lag and why we highlighted arm and hand function in pwMS in our #ThinkHand campaign and why we are doing the CHARIOT-MSORATORIO-HAND and UNDER&OVER trials. In short, we have hypothesised that it is never too late to modify the course of MS.

A few years ago during the #ThinkHand campaign one of my colleagues presented a patient who was had advanced MS (EDSS 7.5 = wheelchair-bound) who was still on interferon-beta. In keeping with NHS England guidelines, she had to stop treating this patient with interferon-beta. Three months later this patient presented with double-vision due to a brain-stem relapse. An MRI with contrast showed multiple Gd-enhancing lesions indicative of reactivation of MS disease activity, or rebound, post-interferon-beta. As this patient was not eligible to be restarted on a licensed DMT, we at the MDT recommended that the patient be offered off-label treatment with generic subcutaneous cladribine. Our position was that although the patient may be wheelchair-bound with advanced MS, she still had upper limb (arm & hand) and bulbar (swallowing and speech) function to preserve. Were we wrong to treat this patient and assume that the therapeutic window to modify her disease course has shut? This patient is not unique and almost every MS expert will have similar cases. 

As a result of these and other insights we are challenging the NHS England DMT stopping criteria, are proposing a randomised controlled trial to evaluate whether or not MS is modifiable in the population of patients who have to stop their licensed DMT.  Are these ‘unsalvageables’ salvageable? 

In short, we propose randomising pwMS who are forced to stop their existing DMT to treatment with possible generic cladribine or placebo with the primary outcome being NEDA or disease progression as defined using upper limb function, i.e. the 9-hole peg test. The plan is to make this an event-driven trial and if someone reaches the study end-point they can be unblinded and offered a course of cladribine if they were previously treated with placebo. If they had broken through on cladribine they could be offered a further course of treatment or another off-label salvage therapy, for example, rituximab biosimilar. 

Instead of assuming MS is not modifiable beyond a certain stage should we not at least try and salvage upper limb function in people with more advanced MS?

The real question is do we have the equipoise to do this study? Please note that in a small French study, 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 confirm disability progression was significantly shorter among DMT stoppers than stayers. The data from these two studies would indicate that we should ignore NHS England because their stopping criteria are not evidence-based and give the patient the option of stopping their DMT or continuing with it. What do you think? 

Length-dependent axonopathy

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Review Mult Scler Relat Disord. 2017 Feb;12:70-78.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and an S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

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.

Conflicts of Interest

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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 and are not meant to be interpreted as personal clinical advice. 

#TeachMS: new treatment strategies

If you are free this Thursday you may want to listen to Mark Freedman and me discussing different treatment strategies in relation to managing MS in the current environment. All of our discussions will be case-based. Please register as there are limited places available.

CoI: multiple

Derisking anti-CD20: the ADIOS-IM study

Barts-MS rose-tinted-odometer: ★★★★★ (a London Grey day #666677)

Can we use an anti-CD20 therapy as an immune constitution therapy (IRT), i.e. 2 years of treatment followed by no treatment unless there is EIDA (evidence of inflammatory disease activity)? This strategy is not new to the field of MS; this is how we use alemtuzumab, cladribine and AHSCT. So why not with ocrelizumab, ofatumumab or rituximab?

The anti-CD20-IRT question really needs an answer. However, many of my colleagues are nervous about not treating pwMS continuously and would therefore prefer to use adaptive dosing of anti-CD20s based on B-cell, or memory B-cell, reconstitution. This is why we proposed doing the ADIOS study (adaptive ocrelizumab dosing study) in 2019 and were in the process of getting this study designed and funded prior to COVID-19. 

However, since COVID-19 and the introduction of COVID-19 vaccines have spotlighted the long-term safety signals associated with continuous anti-CD20 therapy and their associated poor vaccine responses we now want to redesign the study. We now want the study to be focused on safety and to add another arm to test using anti-CD20 therapy as induction therapy for 2 years and then following it with a derisking strategy using one of the licensed immunomodulatory or low-risk maintenance therapies, i.e. interferon-beta, glatiramer acetate, teriflunomide or dimethyl fumarate (DMF). This is the so-called IM or induction-maintenance arm.

The proposed primary outcome will be serious Infections, which are those requiring hospitalisation. Secondary outcomes will include the development of hypogammaglobulinaemia, antibiotic and antiviral drug usage as a surrogate for infections, vaccine responses, days off work and healthcare utilisation. With regard to efficacy, we propose assessing change in T2-lesion volume or number and relapses for inflammation and brain volume change and disability progression as end-organ damage markers. 

This study will need to be pragmatic and run through a registry, for example, the UK’s OPTIMISE pharmacovigilance platform. We also propose doing some nested or add-on studies in cohorts to do specific vaccine, biomarker, immunology and virology studies. These add-on studies will provide more data on each of the arms being used in the ADIOS-IM study.

Some questions for any readers who are anti-CD20 therapies. Would you volunteer to participate in this study? If there are any HCPs reading this post do you think we have clinical equipoise to do this study or have you already adopted one or more of these strategies to derisk anti-CD20 therapy already in your clinical practice? 

Another potential advantage of this study, apart from making your MS treatment safer, is the potential cost-saving in the long term for the NHS or your health insurance provider.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

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 and are not meant to be interpreted as personal clinical advice.

Please, please, please #GetVaccinatedASAP

Barts-MS rose-tinted-odometer: ★ (Black & White Friday)

As the delta variant of SARS-CoV-2 is surging it is putting residents of Whitechapel at serious risk of getting COVID-19.

This is important because the vaccination rate in Whitechapel is so low; less than 30% of adults have both dose of the COVID-19 vaccine.

Why is the uptake of vaccines so low in our local community?

Vaccine hesitancy is very high in Whitechapel and the reason are complex. If you can do anything to encourage people to get vaccinated please do. We in Barts Health NHS Trust and the Royal London Hospital are bracing ourselves for another surge of COVID-19 admissions, but the knock-on effects on other services, including our MS service, will take its toll on staff and people with MS.

The following are a some answers to questions that vaccine hesitators may ask. if you are a hesitator are there any questions I have missed out?

The following Questions and Answers have been adapted from the Quinn &  Andrasik perspective in this week’s NEJM.

How did these trials move so quickly?

Researchers used existing clinical trial networks.
Manufacturing started while the clinical trials were still underway.
Adenoviral and mRNA vaccines are faster to produce than traditional vaccines.
Other sponsors use platforms that have proven successful in the development of vaccines.
The studies included more participants than a typical study and disease transmission rates were high, enabling researchers to determine efficacy in a short time.
The MHRA prioritized review, authorization, and recommendation of Covid-19 vaccines.

Were vaccines tested on people like me?

Yes.
Vaccine trials included all adults >18 yr of age.
It was mandated that a large number (~20-25%) of participants in most trials had to be >65 yr of age.
Study participants included ~25% of people with common health problems such as high blood pressure, diabetes, HIV, and cancer.
There were no exclusions for diseases or medications, except immunosuppression.
Vaccine studies did not include pregnant people.

Do these vaccines work for all races/ethnic groups?

Yes. There is strong evidence that the vaccines work well for all people, regardless of their genetic background.
What types of reactions have been reported after vaccination?
Common reactions: Sore arm, headache, aches, fever may appear within 48 hours. These are similar to reactions seen after shingles and influenza vaccines.
Rare reaction: anaphylaxis, blood clots
Current recommendation: 15 minutes of observation after injection
If you have a history of severe allergies or an anaphylactic reaction to a vaccine, it’s recommended that you discuss vaccination with your provider and undergo 30 minutes of observation after receiving the vaccine.
Most people with a history of allergies or anaphylaxis have received a vaccine with no issues.

Should I get a vaccine now or “wait and see”?

You should be vaccinated as soon as possible.
You are not the first:  Over 1 billion people have received COVID-19 vaccines
Immunity takes time to develop and you are only maximally covered against the new variants of the virus about 2 weeks after your second or booster dose of the vaccine. 
Please note the new Covid-19 strains are more contagious and cause more severe disease than the old variants.

Does mRNA and adenovirus DNA change your DNA?

No; mRNA and  adenoviral DNA is a signal to your cell. It stays in the outer part of the cell and does not enter the nucleus where your nuclear DNA is located.
The mRNA and adenoviral DNA in the vaccine is present in the body for only 1–3 days; then it degrades and the immune system is primed and ready.

I’ve heard that the vaccines ….?

No, it will not give you Covid-19.
No, it does not affect women’s fertility.
No, it does not contain fetal tissue, microchips, or any other devices.

Which vaccine is the best?

All the vaccines are very good at preventing severe disease, so they will greatly reduce rates of severe disease progression, hospitalization, and death. When you are offered a vaccine, you should take it. Because the adenoviral vaccines are associated with rare blood clots, which is mainly in younger people (<30), it is recommended that young people have the mRNA vaccines (Pfizer or Moderna). 

Why do I have to wear a mask after getting immunized against Covid-19?

The vaccines prevent Covid-19 disease, severe disease, and death.
We know much less about whether vaccines prevent asymptomatic infection, as this question was not studied. Until we know that, we must assume that vaccinated people might get Covid-19 and not know it.
Masks, social distancing  and handwashing are still required until we have more information.

Is one dose of  vaccine as effective as two doses?

The data are very clear that the best protection from Covid-19 disease happens after the second (booster) dose.
The first dose starts the immune response, and the second dose boosts it to make high antibody levels.

How long does vaccine immunity to Covid-19 last?

We don’t know. Covid-19 is a brand-new human disease, and we will need more time to determine how long vaccine responses last.

How will viral mutations affect Covid-19 vaccines?

Current vaccines work well against the variant originally identified in the UK.
There seems to be some reduced efficacy for the variants originally identified in South Africa, Brazil and India. 
The vaccines are still highly effective in preventing severe disease (reducing risk of being hospitalised, requiring supplemental oxygen, needing a ventilator) and death.
The vaccines may not prevent you from getting mild symptoms, but they will prevent severe disease.

Please get out there and become a pro-vaccine warrior. The sooner we flatten the tail of this pandemic with vaccine immunity and not herd immunity form wild-type infection the lower the risk of immune escape variants and the fewer deaths.

Quinn &  Andrasik. Addressing Vaccine Hesitancy in BIPOC Communities — Toward Trustworthiness, Partnership, and Reciprocity. N Engl J Med 2021; 385:97-100. 

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

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 and are not meant to be interpreted as personal clinical advice. 

73 tomorrow – some achievement

Barts-MS rose-tinted-odometer: ★★★★★ (Today’s colours are NHS blue & yellow #005EB8 & #FAE100)

Tomorrow the NHS turns 73. If you love the NHS and want to give it and its staff a present please have your COVID-19 vaccine. Barts Health NHS Trust and many other NHS services are running walk-in vaccine centres.

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We are now in the long tail of this pandemic and the sooner we all get vaccinated the sooner the curve will flatten and the tail will get shorter.

Thank you.  

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

Twitter   /  LinkedIn  /  Medium

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 and are not meant to be interpreted as personal clinical advice.

Ask not

Barts-MS rose-tinted-odometer: ★★★★ (black&white)

I once proposed the question, “ask not what your healthcare professional (HCP) or MS research community can do for you, but what you can do for yourself?” and had quite a lot of pushback from some readers. Why?  

I started developing this diagram more than a decade ago summarising the holistic management of MS. What I mean by this is that if we, or more importantly you in partnership with your HCP, address every item on this diagram you should be able to optimise the management of your MS and maximise your brain health. 

Surely the therapeutic aim in MS must be to get every person with MS to old age with as healthy a central nervous system as possible so that you can age normally. I find it difficult to communicate such a long term target to my patients and their families because most people, including the healthcare community,  have relatively short or intermediate-term goals.

Please note the diagram on the holistic management of MS is not all black-and-white but has some shades of grey. The reason for the grey boxes is that we are not there yet in terms of having licensed treatments, but we are working on them. You may realise that this diagram covers the management of not only active MS, but smouldering disease as well.

Please note there is some overlap between MS-specific targets and non-MS or brain health targets, for example, exercise is neuroprotective and promotes remyelination and recovery. Every item on the diagram above has been covered before on this blog so nothing should come as a surprise to you unless you are new to the blog.

Are you up for taking on the ‘Holistic Management Challenge’ yourself? Do you have enough information? Do you have enough support from your HCP to do so? 

Conflicts of Interest

Preventive Neurology

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Medium

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 and are not meant to be interpreted as personal clinical advice. 

Second opinion

Barts-MS rose-tinted-odometer: zero-★s (black Monday; playing roulette with your patients’ brains)

I recently saw a patient for a second opinion. He was about to start dimethyl fumarate (DMF), but his wife who had spent a lot of time reading about MS wanted him to be treated with something more effective. She had read the MS-Blog (formerly the Barts-MS Blog) and wanted him to have a higher efficacy DMT.

He is only 43 years of age and has had MS for at least 12 years. He had an episode of transverse myelitis when he was 31. At the time his MRI of the brain had no MS-like lesions, but in retrospect, there was subtle brain volume loss; his so-called Sylvian fissures were much too large for a 31-year-old and he had largish lateral ventricles (the fluid-filled spaces in the brain). The clue to the diagnosis of MS was in the spinal fluid analysis that showed the local synthesis of oligoclonal IgG bands; these can now be used in the diagnosis of MS to indicate dissemination in time. This patient was sent away and told to come back if he developed any new symptoms. He did come back with an episode of vertigo and unsteadiness of gait 12 years later. His MRI of the brain was full of MS lesions and he had gross brain volume loss. He was told by his neurologist that he now had relapsing-remitting MS and was eligible for treatment and been offered DMF.

When taking a neurological history this patient had had numerous symptoms that indicated he had had several attacks in the last 12 years. An episode of sharp shooting pains in legs, a period of urinary frequency and urgency, an episode when he had noticed difficulty running with a partial dropping of his right foot. All of these were clearly relapses, which he ignored. The onus of reporting these symptoms had been put on the patient. Maybe things would have turned out differently if he had been seen annually and had regular monitoring MRIs.

On our video consultation, he said he was fully functional, working full-time and had no problems with activities of daily living. This was in keeping with his neurologist’s clinic letter that didn’t mention any abnormal neurological signs and the letter actually played down the MRI findings, by not even mentioning the gross brain atrophy that had been reported by the neuroradiologist on the current MRI.

As I was doing this consultation via a video platform something told me I need to examine this patient. I arranged a face-2-face consultation and when I saw this patient a few weeks later his neurological examination was far from normal. He has jerky eye movement with square-wave jerks indicative of cerebellar involvement. He had bilateral optic disc pallor indicative of optic nerve involvement. He was unable to walk heel-to-toe due to an unsteady gait and he had a positive Romberg’s test, i.e. his body swayed from side to side when he closed his eyes and he would have fallen if I had not told him to open his eyes. He had mild triparesis; i.e. weakness in three out of four limbs. He also had clear cerebellar signs with incoordination in both upper limbs with a mild intention tremor. Finally, he had impaired joint position sensation in the joints of the big toe. 

On taking his history again he now volunteered mild to moderate urinary frequency and sexual dysfunction. His wife who attended with him told me that he had had to stop running a few years ago because of exercise-induced left foot drop, which had been getting worse and now was visible after 2-3 km of walking. She also mentioned limb jerks in bed at night, nocturia and that he had become very forgetful and was having difficulty at work. 

It is clear this gentleman has advanced MS with severe end-organ damage affecting all functional systems. Sadly he has been let down by the system. He should have been told upfront it is likely he had MS. Just maybe cognitive testing and a set evoked potential 12 years ago would have shown dissemination in space and he would have been diagnosed with MS and treated. Instead, his diagnosis of MS has been delayed by 12 years. Based on his history and examination this paint has secondary progressive MS (SPMS). 

Should I label him as having active SPMS and offer him siponimod? Should I say he has highly active MS or rapidly evolving severe MS and try and manipulate the NHS England treatment guidelines to offer him a choice of several high efficacy DMTs? Should I just take the path of least resistance and offer him ocrelizumab or ofatumumab the two very high-efficacy DMTs that can be used first-line in the NHS? Should I not offer him a licensed DMT and refer him for possible enrollment into the high-dose simvastatin trial?

What this pandemic has taught me is that my real skill, which won’t be replaced soon by a robot, is doing a neurological examination and eliciting signs of end-organ damage and then integrating this information with the history, MRI and other investigations. I wonder if the many MS self-monitoring applications that are emerging would have detected and interpreted the clinical examination the way I have done with this patient? 

Interestingly, when I examined this patient he told me that his neurologist,  apart from getting him to walk and test his eye movements, had not done a detailed neurological examination. This is not unusual in clinical practice; in fact, one of our colleagues at the Royal London Hospital has even argued for us not doing the neurological examination at all as it doesn’t add much to either the diagnosis and/or management of his patients. Do you agree with him? 

Christopher H Hawkes. I’ve stopped examining patients! Pract Neurol. 2009 Aug;9(4):192-4.

If you are interested in finding out about what changes to our MS services from the pandemic will stick I suggest you log into the webinar that I am doing later this week with Trishna Bharadia when we will be discussing the impact and changes the pandemic has had om MS services and what I think will change. What is clearly not going to go away is the need for face-2-face consultations and neurological examinations. But then this is referring to my take on things and I may not be correct.

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CURE-3

Barts-MS rose-tinted-odometer: ★★★★★ (still seeing red, despite Summer having finally arrived)

I am considering retraining as a medical philosopher. The thinking of the MS research community is riddled with fundamental errors that could be sorted out by applying basic philosophical principles. One example is the diagnostic tautology we are wedded to in how we define MS as a disease. Another relates to the classification of categorical MS disease states. Defining an MS cure, etc. I am also being criticised for supporting two conflicting, juxtaposed theories about the potential cause of MS. How can I ‘believe’ MS is caused by EBV and at the same time talk about IRTs (immune reconstitution therapies) potentially curing MS as an autoimmune disease.

The reality is that scientists are not religious and don’t hold beliefs. Scientists put forward hypotheses, which are then tested and refined. Over time hypotheses get rejected and/or evolve and if the experimental evidence becomes overwhelming they enter the canon of human knowledge as facts. In comparison, beliefs are immutable and cannot be challenged. Therefore, I don’t believe EBV is the cause of MS and I don’t believe MS is an autoimmune disease. I hypothesise that EBV is the cause of MS, I hypothesise that MS is an autoimmune disease and I hypothesise that these two theories are not mutually exclusive, i.e. MS can be caused by EBV and still be an autoimmune disease. In other words, EBV is the driver of autoimmunity and by removing EBV from the MS causal pathway you prevent or cure MS. 

To prevent EBV infection we are exploring doing an EBV vaccine trial in people at high risk of MS and then following them to see if they go on to develop MS or not. This experimental paradigm is well-rehearsed and relatively easy to understand. 

What is not easy to understand is how EBV causes MS. One theory is that EBV simply provides autoreactive B-cells and T-cells with a survival advantage and as a result, they persist, expand in numbers and become dysregulated, which tips over into autoimmunity that becomes self-perpetuating. How EBV does this is not known. One mechanism that I have proposed is that because EBV infection causes B-cells and T-cells to hyperproliferative, i.e. go through many cell divisions, they acquire so-called somatic mutations in their genomes that sets the stage for autoimmunity.

There is mounting evidence in MS that the majority of pwMS have somatic (in the body and not in the germline) mutations in T-cells and B-cells (see studies below). These mutations could provide these cells or clones with a survival advantage, based on simple Darwinian selection principles, which explains why they persist and expand in number. Think of these cells as being like a kind of benign tumour. The important thing is that these cells can be killed using aggressive immunodepletion strategies such as AHSCT or alemtuzumab treatment. 

Another thing to remember is that it may not be one but several somatic mutations that are required to trigger autoimmunity. So if you purge the downstream autoimmune clones, but leave the upstream driver clones behind, they may have the potential to acquire new mutations and hence reactivate autoimmunity in the future. This could explain why some people who go into long-term remission after HSCT or alemtuzumab treatment breakthrough many years later with recurrent MS disease activity. 

The two studies below show that pwMS harbour many somatic mutations in their circulating B-cells and T-cells. These data not only underpin the hypotheses presented above, but also support the hypotheses that MS is an autoimmune disease triggered by EBV and that it can be cured by an immune reconstitution therapy. 

So I won’t be deterred by my campaign to define what an MS cure looks like so that we can look for it and claim it as a victory in the management of this awful disease

Yes, I am a big supporter of the hypothesis that MS is a curable disease and this position is absolutely compatible with my positions on the role of EBV and autoimmunity in causing MS. Do you disagree?

The great tragedy is that if IRTs cure MS in a proportion of pwMS, why are we not using IRTs more widely? Now that is the big story that can be told another day.  

Our current approach to treating MS. Photo by Luis Villasmil on Unsplash

van Horebeek et al.  A robust pipeline with high replication rate for detection of somatic variants in the adaptive immune system as a source of common genetic variation in autoimmune disease. Hum Mol Genet. 2019 Apr 15;28(8):1369-1380.

The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives, and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0.5% and achieves a replication rate of >55%. Validation in an independent data set demonstrates excellent performance (sensitivity > 57%, specificity > 98%, replication rate > 80%). We applied this pipeline to the autoimmune disease multiple sclerosis (MS) as a proof-of-principle. We demonstrate that 60% of MS patients carry 2-10 exonic somatic variants in their peripheral blood T and B cells, with the vast majority (80%) occurring in T cells and variants persisting over time. Synonymous variants significantly co-occur with non-synonymous variants. Systematic characterization indicates somatic variants are enriched for being novel or very rare in public databases of germline variants and trend towards being more damaging and conserved, as reflected by higher phred-scaled combined annotation-dependent depletion (CADD) and genomic evolutionary rate profiling (GERP) scores. Our pipeline and proof-of-principle now warrant further investigation of common somatic genetic variation on top of inherited genetic variation in the context of autoimmune disease, where it may offer subtle survival advantages to immune cells and contribute to the capacity of these cells to participate in the autoimmune reaction.

Valori et al. A novel class of somatic mutations in blood detected preferentially in CD8+ cells. Clin Immunol. 2017 Feb;175:75-81.

Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4+, CD8+, CD19+ and CD4-/CD8-/CD19- cell subpopulations were separated. We performed next-generation DNA sequencing targeting 986 immune-related genes. Somatic mutations were called by comparing the sequence data of each cell subpopulation to other subpopulations of the same patient and validated by amplicon sequencing. We found non-synonymous somatic mutations in 12 (60%) patients (10 MS, 1 myasthenia gravis, 1 narcolepsy). There were 27 mutations, all different and mostly novel (67%). They were discovered at subpopulation-wise allelic fractions of 0.2%-4.6% (median 0.95%). Multiple mutations were found in 8 patients. The mutations were enriched in CD8+ cells (85% of mutations). In follow-up after a median time of 2.3years, 96% of the mutations were still detectable. These results unravel a novel class of persistent somatic mutations, many of which were in genes that may play a role in autoimmunity (ATM, BTK, CD46, CD180, CLIP2, HMMR, IKFZF3, ITGB3, KIR3DL2, MAPK10, CD56/NCAM1, RBM6, RORA, RPA1 and STAT3). Whether some of this class of mutations plays a role in disease is currently unclear, but these results define an interesting hitherto unknown research target for future studies.

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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.

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