Category: Archive

Barts-MS rose-tinted-odometer: ★★★ (gray Friday; overcast and miserable #3a3b3c)

It was not easy writing this blog post; I hope it makes sense. I was asked the other day ‘what defines a low versus a high-dose B-cell depleting anti-CD20 therapy?’.

Unlike with small molecules the dose of monoclonal antibodies is not necessarily about drug/antibody levels, but how much of the target gets inhibited or depleted and then how long these effects last. So when I compare ocrelizumab (600mg intravenously every 6 months) with ofatumumab (20mg subcutaneously every month) is there a difference? Yes and no; it depends on whether or not you take into account the potential CNS effects of these agents.

No in the sense that both of these doses are likely to keep circulating peripheral B-cell numbers very low and seem to have similar effects when it comes to suppression of inflammatory MS activity, i.e. relapses, focal MRI lesions, relapse associated-worsening and possibly even a component of PIRA (progression independent of relapses). 

It is clear that ocrelizumab is a higher dose and is having a greater effect on deep tissue B-cells. The half-life of circulating monoclonal antibodies is partially determined by the circulating concentration vs. the quenching effect of the target antigen. The more circulating antibody around, the longer its half-life. The more target antigen around, i.e. CD20+ B-cells, the lower half-life of the antibody because the antigen binds to and removes antibody from the circulation. Following B-cell depletion, the half-life at steady state for ofatumumab is estimated to be approximately 16 days (FDA ofatumumab prescribing information) compared to  26 days for ocrelizumab (FDA ocrelizumab prescribing information). 

Other differences supporting the low vs. high dose differences relate to B-cell repopulation kinetics. For ofatumumab B-cell counts reach the lower limit of normal in at least 50% of patients in 24 to 36 weeks after stopping treatment, which equates to a median time to B-cell recovery of ~40 weeks post-treatment discontinuation (FDA ofatumumab prescribing information). For ocrelizumab, the median time for B-cell counts to return to either baseline or the lower limit of normal is 72 weeks (range 27-175 weeks) (FDA ocrelizumab prescribing information).

Based on the above there is little doubt that ocrelizumab is higher-dose than ofatumumab. Is this relevant? I think it may be if part of the mode of action of B-cell depletion therapies is to target B-cells and B-cell follicle-like structures within the CNS of pwMS.  The amount of antibody that crosses the blood-brain barrier is roughly 0.5% of what is circulating in the periphery; as steady-state levels are higher with ocrelizumab more of it is likely to cross the blood-brain barrier and affect CNS and meningeal B-cells.

We are only one of many groups that hypothesise that the intrathecal or CNS B-cells, plasma cells and antibodies (oligoclonal bands) are pathogenic in MS and are driving some of the smouldering pathologies we see in MS. This is why we are exploring therapies such as proteasome inhibitors (ixazomib), cladribine, BTK inhibitors and high-dose ocrelizumab to see if we can scrub the CNS clean of OCBs. So yes, based on this hypothesis I think the dose of ofatumumab may be too low to affect intrathecal B-cells. A clue to this is that there was no dose effect, based on body size, on disability progression noted with ofatumumab compared to that seen with ocrelizumab. Why?

Dose-response relationships in biology are often S-shaped. I suspect the intrathecal effects of ofatumumab based on body size is on the flat part of the S-curve. In comparison with the higher body-size based doses of ocrelizumab, the intrathecal/smouldering MS effects are on the linear part of the curve and hence why there is a clear signal (see dosing imaging below). There is a way to investigate this hypothesis involves doing detailed CSF studies comparing what happens within the spinal fluid of patients on ocrelizumab high-dose vs. ocrelizumab standard-dose vs. ofatumumab standard-dose. I hypothesize there will be a clear ladder on the impact on CNS B-cell biology. At the same time, we can ask what is the impact of this anti-CD20 dosing tier is on meningeal B-cell follicle-like structures, slowly expanding lesions, subpial cortical lesions, brain volume loss, CSF NFL levels, etc.?

So yes, I do think ofatumumab is a low-dose anti-CD20 therapy and ocrelizumab is a higher-dose anti-CD20 therapy. This explains why I helped push/nudged Roche-Genentech to design and run their own version of our proposed DoDo (double-dose) ocrelizumab study. The good news is that these high-dose ocrelizumab trials are recruiting rapidly and we should have an answer to some of these questions in the next 3-4 years.

Based on the above I am also against low-dose rituximab dosing in MS. I think we need high-dose CNS-penetrant anti-CD20 therapies; at least initially. Once you have purged the CNS of B-cells and B-cell follicle like structures the dose can probably be reduced. 

Please, let me know if this post makes sense? Thanks.  

CoI: Please note I sit on the steering committee of Roche-Genentech’s high-dose ocrelizumab programme. 

Conflicts of Interest

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. 

Barts-MS rose-tinted-odometer: ★★

In the last 2-3 years I have been talking about the need for the MS community to treat-2-target beyond NEDA (no evident disease activity) to try and prevent end-organ damage. Yes, we need to protect the end-organ in MS just as the nephrologists try to protect the kidney in autoimmune kidney disease and the rheumatologists the joints in rheumatoid arthritis (RA). 

However, in a very similar way to MS if you let too much damage accumulate in the kidney or RA joint self-perpetuating mechanisms are set up that lead to slow deterioration in kidney and joint junction and they eventually fail. Fortunately for nephrologists, you can put patients with kidney failure on renal dialysis (an artificial kidney) or offer a kidney transplant (substitute kidney) and in RA you can replace the joints. In comparison, in MS you can buy walking sticks, walkers, wheelchairs and exoskeletons, but you can’t repair and restore lost neurological function. This is why the ‘diagnose early, treat early, treat effectively’ message is so important. Yes, time really is brain. 

There is a longstanding theory that the biology of MS changes with time. So with time as the inflammatory infiltrates within the central nervous system increase, B-cell follicle-like structures develop, plasma cells take up residence, oligoclonal IgG bands appear and increase in number, microglia become diffusely activated, slowly expanding lesions or SELs increase in number, astrocytes get activated and form glial scars, demyelination increases, remyelination fails, axonal and cortical plasticity decrease and synaptic pruning increase the die is set and the course of MS becomes unmodifiable with our current DMTs. In essence ‘smouldering MS’ becomes the real MS and we can’t modify it.

In the Queen Square longitudinal CIS study (see below) the EDSS score at 14 years correlated with the lesion volume on MRI at 5 years and the increase in lesion volume over the first 5 years. In the London Ontario natural history study it was the number of relapses in the first two years that predicted poor outcome. So pwMS who only had 1 relapse in the first 2 years compared to those who had 3 or more relapses took 7.6, 12.8 and 20.3 years longer to reach EDSS scores 6 (walking stick), 8 (bed) and 10 (death), respectively. Also, subjects who developed early disability, i.e. EDSS 3.0, become disabled quicker, i.e. they reached higher EDSS scores much quicker than those who don’t develop early disability. In other words, disability begets disability. 

Therefore the clinical philosophy of watchful-waiting is hardly practised anymore even in patient’s who are diagnosed with clinically isolated syndrome (CIS). If patients with CIS have high-risk scans, i.e. lesions on the scan that look like demyelinating lesions, most neurologists now feel obliged to offer these patients treatment.  A big debate now is how aggressively do you treat people with CIS. Do you simply start them on a safe platform therapy? Or do you hit their disease with a potent IRT? I would argue the latter but instead of using alemtuzumab or HSCT, I would recommend something like oral cladribine. However, this is not possible, cladribine is not licensed for CIS and the current NHS England treatment algorithm is quite clear that we shouldn’t treat CIS. 

Treatment Algorithm for Multiple Sclerosis Disease-Modifying Therapies (NHS England Reference: 170079ALG, Date Published: 4 September 2018, Updated: 8 March 2019 Gateway reference: 07603)

‘Trials of first-line therapies in people with the original definition of Clinically Isolated Syndrome (CIS) at high risk of conversion have NOT shown a convincing long-term effect on the accumulation of disability. In 2018, NICE concluded that it was “unable to make recommendations for treating clinically isolated syndrome because the diagnostic criteria for multiple sclerosis and clinically isolated syndrome have changed and the treatment pathway has evolved”. These new diagnostic criteria are the 2010 and 2017 McDonald criteria.’

Fortunately, the number of patients presenting with a clinical event who have CIS is now very small and most of them have MS after underground a lumbar puncture and are shown to have CSF OCBs or convert to becoming MS very quickly. The question for pwCIS is how much damage will occur in the time window between presentation with CIS and conversion to MS and is this watchful waiting period of time long enough to allow the biology of MS to change, i.e. for smoulder MS pathology to take up residence in the CNS?

The question therefore remains is how early is early when it comes to treating MS? I would argue as early as possible, which is why when we were approached to be a trial centre to assess a very high efficacy DMT in RIS (radiologically isolated syndrome) or asymptomatic MS we said yes. 

I would be interested to know how many of you who had been diagnosed with CIS were treated immediately, how many of you were asked to watchfully wait before being offered treatment and how many of you still have CIS? 

Brex et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med. 2002 Jan 17;346(3):158-64. doi: 10.1056/NEJMoa011341.

Background: In patients with isolated syndromes that are clinically suggestive of multiple sclerosis, such as optic neuritis or brain-stem or spinal cord syndromes, the presence of lesions as determined by T2-weighted magnetic resonance imaging (MRI) of the brain increases the likelihood that multiple sclerosis will develop. We sought to determine the relation between early lesion volume, changes in volume, and long-term disability.

Methods: Seventy-one patients in a serial MRI study of patients with isolated syndromes were reassessed after a mean of 14.1 years. Disability was measured with the use of Kurtzke’s Expanded Disability Status Scale (EDSS; possible range, 0 to 10, with a higher score indicating a greater degree of disability).

Results: Clinically definite multiple sclerosis developed in 44 of the 50 patients (88 percent) with abnormal results on MRI at presentation and in 4 of 21 patients (19 percent) with normal results on MRI. The median EDSS score at follow-up for those with multiple sclerosis was 3.25 (range, 0 to 10); 31 percent had an EDSS score of 6 or more (including three patients whose deaths were due to multiple sclerosis). The EDSS score at 14 years correlated moderately with lesion volume on MRI at 5 years (r=0.60) and with the increase in lesion volume over the first 5 years (r=0.61).

Conclusions: In patients who first present with isolated syndromes suggestive of multiple sclerosis, the increases in the volume of the lesions seen on magnetic resonance imaging of the brain in the first five years correlate with the degree of long-term disability from multiple sclerosis. This relation is only moderate, so the volume of the lesions alone may not be an adequate basis for decisions about the use of disease-modifying treatment.

Scalfari et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010 Jul;133(Pt 7):1914-29.

The relationship of relapses to long-term disability in multiple sclerosis is uncertain. Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation. We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort. Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing-remitting phase. Survival was compared among groups stratified by (i) early relapses–number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing-remitting phase. Early clinical features can predict hard disability outcomes. Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints. Attack frequencies, in the first 2 years, of 1 versus >or=3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively. Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10. In contrast, neither total number of relapsing-remitting phase attacks nor of relapses experienced during the relapsing-remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints. The failure of a regulatory mechanism tied to neurodegeneration is suggested. Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome. These appear to be separated by a watershed within the relapsing-remitting phase, just a few years after clinical onset. Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression. They increase the probability of its occurrence, its latency and influence–to a lesser degree–its slope. The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing-remitting patients.

Conflicts of Interest

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.

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.

Conflicts of Interest

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.

A reminder that we are hosting the Barts-MS Question & Answer session on COVID-19 vaccines and our vaccination policy from 16h30-17h30 this afternoon. We will be live-streaming the event via YouTube. If you can’t watch the event live it will be recorded and remain available for asynchronous viewing at your leisure.

As of yesterday we had received 111 questions; too many to get through in an hour. However, there were many repeats. I will be joined by Prof K (Professor of Neurology), MD1 (mouse doctor and immunologist), Dr Saul Reyes (neurologist and MS vaccine expert), Joela Mathews (neuroscience pharmacist) and Andrea Stennett (neuro-physiotherapist).

CoI: multiple

Barts-MS rose-tinted-odometer: ★★★★★

About 5 or 6 years ago, when we decided to replace the term DAF (disease-activity free) with NEDA (no evident disease activity) as a treatment target MS we created space to allow us to ‘move the goalposts’, i.e. to let our treatment targets in MS evolve as new insights and new technologies emerged. 

This is particularly pertinent as the field now realises that MS is not relapses and MRI activity (Gd-enhancing and new T2 lesions), but other processes that underlie this. I refer to this as smouldering MS or the real MS. This is why we no have to develop treatments that slow or stop the accelerated end-organ damage that defines smouldering MS. 

Please note  that I say accelerated end-organ damage, because life in itself is a neurodegenerative disease. As part of the normal ageing process the end-organ (brain, spinal cord and periperipheral nervous system) gradually degenerate over time. Most people class ageing as a normal phenomenon, but it is clear that ageing is modifiable and that  there are well-defined biological processes that drive ageing that can be targeted to slow down the inevitable decline associated with getting old. I think unhealthy ageing should be classified as a disease and treated as such. 

So what can you do to slow down accelerated ageing? Most of the interventions at present relate to lifestyle interventions in particular diet and exercise. Which diet? I have discussed this previously and I think the scientific evidence supports caloric restriction, intermittent fasting and ketogenic diets as those most likely diets to modify ageing. Caloric restriction is not really feasible over a lifetime, which is why I promote intermittent fasting and ketogenic diets. The good news is that there are some preliminary trials that are looking into these diets in MS. I doubt these trials will be definitive, but they are likely to show that both intermittent fasting and ketogenic diets are at least safe in pwMS. 

There is also emerging data that the pathways these diets activate can be activated by drugs, for example, by metformin and fumarates. There are ongoing studies and new trials planned of metformin in MS. As you know dimethyl fumarate and diroximel fumarate are licensed DMTs in MS. Both these DMTs are reasonably effective in MS and a proportion of patients are clearly super-responders to fumarates. I personally think we need to explore combination therapies with fumarates as one of the options in the combination to target smouldering MS. To be honest and pragmatic it is going to be a lot easier to test a cocktail of drugs in smouldering MS  than a diet. 

Other things you can do to tackle accelerated ageing is to prevent getting comorbities (diabetes, hypertension, etc.) or if you have them to make sure they are well controlled. To stop smoking, to consume alcohol in moderation, to improve your sleep hygiene, to reduce your anticholinergic medication load, to consider HRT (hormone replacement therapy), to prevent recurrent infections (chest, urinary tract, mouth, sinusesm etc.) and to make sure you don’t become socially isolated. 

MS as a disease can have a dramatic impact on your social capital, i.e. the number of meaningful relationships you have. We now know that people with large social networks have better outcomes. Barts-MS have started investigating ways of helping our patients expand their social networks as a treatment strategy for MS. 

Most of the messages in this blog post should not be new to you as I have written about all of them in the past, hence the links to other posts. However, it is good to repeat things and to remind you that a lot of what we are saying about the holistic management of MS, to improve long-term outcomes, is in your hands. This is why we self-management is so important. 

Moving the Goalposts 2

As you may know after my recent accident I set myself a challenge, ‘Prof G’s crutches to 500 m Challenge’ to raise money for MS Research. However, I achieved this target yesterday (day 5 after discharge) so I also have had to move the goalposts. My new challenge is  ‘Prof G’s bed to 5km Challenge’; I want to be able to walk 5km without stopping or using support before the 31st December. To achieve this I am hoping my pelvic and cervical spine fractures heal well and the pain subsides. Walking 650 meters yesterday was truly a mammoth challenge for me and I feel worse today (muscle stiffness and pain) than I did after running the virtual marathon last month. So please support me with my new 5km challenge to reach our funding target of £25,000. Please note that all of the money raised will go to Queen Mary University of London to support Dr Ruth Dobson and Dr Angray Kang’s COVID-19 MS Antibody Study. Their study is not only relevant to COVID-19, but will create the platform for remote testing of pwMS using blood spots. We are already planning a raft of other studies using this technology, but more on this later.

Thank you

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

Barts-MS rose-tinted-odometer: ★★★★★

I love science; it is such a thrill. I think science historians will look back at 2020 and the impact COVID-19 has had on science and scientific publishing and will define a new scientific era as being AC19 (after COVID-19) and the other era as BC19 (before COVID-19). The reason why I say this is because some of the changes that COVID-19 has induced in the scientific process such as multi-stakeholder collaborations, data sharing, pre-publication, rapid repurposing and sharing of laboratories and technologies, sharing of hypotheses, thinking aloud, pooled funding, virtual meetings, distributed working, online consenting for trials, streamlining of the ethics and regulatory approvals processes for clinical trials, the reduction in red-tape associated with research, etc. is unlikely to go away. One could argue that all of these individual changes may be small, but add them together and the scientific process is going to be very different after COVID-19; in particular, it is going to be faster.

I sincerely hope the MS community taps into the success of the COVID-19 model of doing science. 

If I was in charge of MS Research, i.e. if I was the MS Research Tsar, I would have an open democratic competition to create a short-list of grand challenges in MS, i.e. hypotheses that need to be definitively tested at scale. I would then set-up an international steering committee of the deep thinkers in MS and make sure the MS politicians are excluded (those people of influence who often dominate these sorts of panels with their self-interests and blinkered and group thinking). These panels will have all their meeting in the open, i.e. lived streamed. The latter will make the scientific process transparent, which rarely happens and explains why so many MS researchers and research teams feel disenfranchised at present. 

This panel would then select principal investigators to run the research programmes to address the grand challenges. These PIs will need to buy into the grand challenge, i.e. have skin in the game, have a track record in project management and have the necessary peoples skills to get the project done. I would also make sure the projects are milestone driven to have some control over the trajectory and success of the projects. Projects will need to have predefined go-no-go milestones so as not to waste resources. 

I suspect one grand challenge will be vitamin D MS prevention studies. Although this is a daunting grand challenge it is essential that at some point the MS community takes up the challenge. The epidemiology and basic science around vD biology being in the MS causal pathway are so compelling how can we continue to ignore it?  

The following prepublication is very interesting. It shows, using a non-biased screening of compounds, that of  121 compounds identified with activity against SARS-CoV-2, the active form of vD, calcitriol, exhibits potent activity against SARS-CoV-2. In other words, active vD has antiviral effects. Could these antiviral effects have something to do with vD’s role in potentially preventing MS? Could these antiviral effects extend to EBV and infectious mononucleosis? What about vD and HERVs (human endogenous retroviruses)? 

I have so many questions and such limited time to answer them. My recent accident, and lucky escape, has made me realise how fragile life is; we all need to seize the day. Carpe diem!

Mok et al. Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis. bioRxiv doi: https://doi.org/10.1101/2020.06.21.162396

COVID-19, the disease caused by SARS-CoV-2 (1), was declared a pandemic by the World Health Organization (WHO) in March 2020 (2). While awaiting a vaccine, several antivirals are being used to manage the disease with limited success (3, 4). To expand this arsenal, we screened 4 compound libraries: a United States Food and Drug Administration (FDA) approved drug library, an angiotensin converting enzyme-2 (ACE2) targeted compound library, a flavonoid compound library as well as a natural product library. Of the 121 compounds identified with activity against SARS-CoV-2, 7 were shortlisted for validation. We show for the first time that the active form of Vitamin D, calcitriol, exhibits significant potent activity against SARS-CoV-2. This finding paves the way for consideration of host-directed therapies for ring prophylaxis of contacts of SARS-CoV-2 patients. 

PS: Please support my new challenge: “Prof G’s crutches to 500 m Challenge“ we need to reach our target of £25,000 to support Dr Ruth Dobson and Dr Angray Kang’s COVID-19 MS Antibody Study. It is so important we get this study completed before COVID-19 becomes history. Please note that all of the money raised will go to Queen Mary University of London to support MS Research. Thank you.

CoI: multiple

Twitter: @gavinGiovannoni 

Medium: @gavin_24211

Barts-MS rose-tinted-odometer: ★★

The following is some sound, sensible, advice about how to reduce your risk of being exposed to coronavirus on an aeroplane.

Pombal et al. Risk of COVID-19 During Air Travel. JAMA. Published online October 1, 2020. doi:10.1001/jama.2020.19108

Wear a mask, don’t travel if you feel unwell, and limit carry-on baggage. Keep distance from others wherever possible; report to staff if someone is clearly unwell. If there is an overhead air nozzle, adjust it to point straight at your head and keep it on full. Stay seated if possible, and follow crew instructions. Wash or sanitize hands frequently and avoid touching your face.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211