I have been asked many times about how COVID-19 is affecting our MS research programme. The short answer is massively and its true impact is yet to be realised because we are a far way off from anything that feels and looks like normal. We are still paralysed by the threat of a second wave of COVID-19; the social distancing requirements within the NHS means everything is going to be at half-mast and then the knock-on effects on research funding have yet to be felt.
I am having sleepless nights about the covert threats of upcoming redundancies, whether or not our soft money will dry up, which we rely on to support administrative staff and prime research, how would one goes about declaring that you are academically bankrupt and then the massive increase in the teaching workload as we reconfigure all our teaching courses to go online. I have never worked harder and felt more unsettled than I do now.
A good example of COVID-19’s knock-on effects is our #ThinkHand campaign. For those of you who have been following this blog for years should remember it well. The central theme of the campaign ‘is not to write-off people with MS who have lost their lower limb function and are now having to use a wheelchair’. We have hypothesised and put forward a theory that MS is modifiable throughout its course and want to do clinical trials in people with advanced MS who are wheelchair users. The article by Timmermans and colleagues below shows that leg function declines earlier and quicker than arm function in MS, which supports our so-called ‘length-dependent axonopathy model of MS’.
Our #ThinkHand campaign started about 6 years ago and has resulted in the design and funding of two clinical trials targeting advanced MS. ORATORIO-HAND will be testing ocrelizumab in advanced PPMS (i.e. up to an EDSS of 8.0) and CHARIOT-MS that will be testing oral cladribine in advanced MS, including subjects with either SPMS and PPMS with an upper EDSS cut-off of 8.5. In both these trials, we will be using the 9-hole peg test as the primary outcome. The initiation and/or recruitment of subjects for both these trials have been suspended for the last 4 months and is unlikely to restart for another 2-3 months and maybe longer. We are talking about 6 months or more in COVID-19-related delays. If ‘Time is Brain’ or in the case of these trials ‘Time is Loss of Hand Function’ then these delays may mean that many pwMS will have progressed beyond the eligibility cutoffs for these trials.
We are not the only ones that have been affected and maybe it doesn’t help complaining. A very good friend of ours has cancer that is potentially terminal; as a result of COVID-19, her potentially life-saving surgery has been delayed by over 3 months. This week’s BMJ highlights the plight of cancer patients in the NHS and suggests that COVID-19 may result in 45,000 excess cancer deaths. What is the equivalent figure for people with MS? Will it be 10,000 people with MS lose their independence because of the progression of their MS and loss of upper limb function? Or 8,000 people with MS become unemployed because of worsening disability are a result of subclinical worsening cognition?
My philosophy is to simply get up each morning and try and get on with the task at hand. My motivation comes from an unusual source; a book “The Boy, the Mole, the Fox and the Horse” that my wife gave me at the beginning of lockdown. The quote that sums up the right attitude is the one about storms.
“What is the best thing you’ve learnt about storms?”
“That they end”, said the horse.
Timmermans et al. Ten-year disease progression in multiple sclerosis: walking declines more rapidly than arm and hand function. Mult Scler Relat Disord. 2020 Jun 26;45:102343.
Background and aims: From a clinical perspective there is a difference in the decline of arm and hand function and leg function in patients with multiple sclerosis (PwMS). Therefore, this study investigated the course of walking and arm and hand functions in PwMS over the first 10 years after diagnosis, including whether any function declined earlier or faster.
Methods: A long-term prospective follow-up study of an incidence cohort of 156 patients with a definite diagnosis of MS, either non-relapse onset (n=28) or relapse onset (n=128) type. Participants were systematically examined immediately after definite diagnosis, at 6 months, and at 1, 2, 3, 6 and 10 years. Walking was determined with the fast 10-meter timed walk test (10mTWT), arm and hand function with the Action Research Arm test (ARAT) and the nine-hole peg test (9HPT). The 10-year trajectories of walking and arm and hand functions were compared using standardized z-scores.
Results: From 3 years onwards the z-scores of the arm and leg function were visually diverging, with a trend towards significance at 6 years, and at 10 years the 10mTWT z-score is significantly higher than the 9HPT. This difference is more pronounced in non-relapse onset patients than in patients with relapse onset type MS, but present in both groups over the first 10 years. In the non-relapse onset group a difference in z-scores at 10 years post-diagnosis between the 10m TWT and 9HPT was found of -12.94 (95% confidence interval (CI) -20.2 to -5.73) for the right and -10.14 (95% CI -17.3 to -2.93) for the left hand. In the relapse onset group there was a difference at 10 years post-diagnosis of -2.17 (95% CI -3.75 to -0.59) for the right and a difference of -2.29 (95% CI -3.87 to -0.71) for the left hand.
Conclusion: This is the first longitudinal study that shows that walking declines earlier and more rapidly than arm and hand function in patients with MS. These results give important insights that can be linked to the pathophysiological disease process regarding the ascending order of deterioration in patients with MS.
Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. 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 a 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.
CoI: multiple
As I watch my 22 year old daughter’s hands shake, and know that it was around a year ago that she became unable to walk more than a short distance (which thankfully resolved after a few weeks – but we all know that the threat remains, and likely increases over time) it pains me to read your concerns. Deep in my heart I have known these implications would become real – for those with MS in their lives, and in relation to many other illnesses too.
It’s hard to reconcile it psychologically – especially in relation to your child. I had hoped that the traumatic psychological journey of accepting MS in the life journey of my child had reached some point of acceptance – focusing instead on how to keep her as safe and well as possible. How do we now again balance some kind of ‘acceptance’ in this new world, where once again life can be so ‘unfair’ and certainly unkind. . . with fighting to keep progress and hope? Or do we go brave/radical in the face of slowing down of research and prepare / push for HSCT ?
I too have that book, and I too seek grounding and perspective within it. I give it to all young people I know when I think a life moment will make it useful for them.
Keep going Prof G . . . one day, hour, minute at a time – we all appreciate what you do and what you share . . . even when it’s difficult x
Thank you for your kind words.
Prof G,
Don’t fret! It’s taken 50 years for MS researchers to work out that relapses and MRI activity are not the real MS. The delays / disruption caused by Covid 19 are a drop in the ocean when compared to the snail’s pace of MS research.
“Our #ThinkHand campaign started about 6 years ago and has resulted in the design and funding of two clinical trials targeting advanced MS.“ This sums up the lethargy in the MS research world. I wish you would apply your marginal gains approach to the process of taking an MS research idea and then starting a trial to test the hypothesis – did it really need 6 years? Really?
I hope MS researchers have used the home time to write up outstanding papers, clear out garbage (hard copies and stuff on computers), and reflect on what the priorities should be going forward. I suspect Covid 19 will be used as the excuse for lots of things. The slow pace / limited progress in MS research shouldn’t be one of them. Until MS research can address the real MS, one could argue that the last 50 years have been a write-off, blaming Covid 19 is just a deflection.
Yes and no. COVID-19 has stopped non-COVID-19 research in its tracks and diverted massive resources to solving COVID-19. The question of what happens next and how long it will take to get back on track is worrying. What COVID-19 does show is that you can turbocharge research when the need is there and well-defined.
Sid, I agree COVID-19 has provided breathing-space for reflection and focus on what is important. In my mind, there are three main fields of research that need to be turbocharged in MS:
1. MS Prevention
2. Smouldering MS or the real MS
3. Self-management – changing healthcare systems to get pwMS more engaged with their own monitoring and management
Prof G,
Like the term turbocharged. A friend worked for QinetiQ during Gulf War 2 and they churned out hi-tech solutions are mega speed. It wasn’t all about money available, they were given freedom to think / innovate, a rigid timeframe (need it by xx) and a clear purpose (it will save lives / reduce injuries). The problem with MS research is the lack of urgency even though the purpose is to save lives / further damage. There is no deadline so the field can expand and expand – genes, paediatric, gender, viruses, imaging, biomarkers, rehab… With no time limit and a lack of focus on the ultimate goal (save brain tissue from further damage) the field will keep growing. 12 months of Keto and a good pruning is needed for MS research field to become lean and focused.
Shame Qinetiq didn’t come up with a replacement for the Snatch land Rover at the time. The problem with MS research is no matter how good the research, at the end of the day pharma controls what gets to patients and if they’re not interested then it’s dead. This is why we still don’t have neuroprotectants for MS despite many years of research identifying excellent candidates/strategies.
A poor workman always blames his tools!
The mice doctors should have listened to Henry Ford “ If You Always Do What You’ve Always Done, You Always Get What You’ve Always Gotten”
And talking of Storms, here’s a little soothing music.
And commenters from Sidcup will always revert to type.
I prefer, “If you do not shake the bottle, first none will come and then a lottle”
😉
Do you ever give your mouth a chance the other end is working over-time?
Mice,
Please note, my comments are directed at the organ grinder (Prof G) not the monkeys. I’ve given him Rentokil‘s number. He needs a Covid 19 clear out. Enjoy your retirements.
Whatever, Sid.
Have a lovely day 😉
Yes, 6 years is a long time to translate an idea. Just getting the MS community and the funders to adopt the concept took 4-5 years and a lot of effort on our part. Not sure if there was a quicker way of doing this. Some would consider 6 years quite quick. Everett Rogers who pioneered the study of the ‘adoption of innovations’ who think 6 years is very quick.
Not wanting to take confrontational view against sid or MS Team. Here’s a question MS is still a disease of the rich. Have you considered funding a trial by getting donations. Then rewarding those that contribute based on the percentage, dividends made from the cure/treatment discovered? I know I will invest large sums and im not extremely rich but just slightly above middle class! I can think at least 20 rich personalities with ms in this country! All researchers need to get out of this mentality that pharma has them boxed in. Remember there many capital fund investors who understand the riches a revolutionary drug in ms, alziemers etc. Will make.
Prof G – I’m really sorry that you’re having sleepless nights and are feeling crappy. If it’s any crumb of consolation, what you and the team do and report on here is a massive help to your readers. So thank you for getting up and weathering the storm. What can we do to help? I currently feel like I’m having a mid-life crisis combined with the effects of lockdown combined with frustration over my MS treatment. I‘d love to turn my negative feelings into something positive and MS-ass-kicking related but don’t know where to begin, particularly as I’m in a foreign country. If any readers have any ideas – I’d love to hear them. PS – Thanks for the book tip. Sounds like one I need to read. Keep your ears stiff (as the Germans say)!
The impact of covid 19 may be a blessing in disguise. If and when a vacine is proven to be effective in less then a year. There is going to be a lot expectations set for other diseases. Fundamentally research that is not leading to cure and treatment that adds no more efficacy then the previous drugs is going to lose out big time. All these copy b cell and limod dmts are going to seem irrelevant. Change is always good in the long term. But like any revolution not so nice when your living through it.
“I am having sleepless nights”
You already had
If You’re Going Through Hell, Keep Going – Winston Churchill
…arg…(sorry I havnt read the other comments, so keen and incensed was I to post…)
This calls to mind the serenity prayer The Don G (Prof G)
God, grant me the serenity to accept the things I cannot change,
courage to change the things I can,
and wisdom to know the difference.
If I really thought about it though- (and i am after reading that)..,.I’d feel rather annoyed
MS has been around for ages; but as at today’s date; there is no cure, no effective research and evidenced preferred antidepressant; no effective painkillers; we aren’t allowed or given Savitex, and pharma will always be needed for research?!
Erm….so logically, they will never fund a study reasearch for a cure because…, they’ll be halting a billion dollar industry?!
Durr…
So our incredibly hard working, intelligent, verbose, vibrant neurologists; are being funded to justify sledgehammers to crack nuts.
Those sledgehammers being loss of quality of life with ‘professional patient’ (which is a social impediment in itself) being your top achievement.
Show me an independent study that definitely evidences an improvement of quality of life at the 20year mark; following early ingestion of a dmd.
No ? Why? because there isn’t one.
Quality of life is the crux of it?! ….Isn’t it?!
I’d rather fully enjoy amazing experiences, with a wonky eye and a wobbly gait; a numb foot and a disposable catheter hidden in my knickers; without the millstone of medication and professional patient dominating and defining my life and relationships.
So I’ll pay for it in five years?
Whose to say it wouldn’t happen anyway?
I’ve got better things to do with my time that being talked down to, patronised and pitied on a regular basis (neurologist ) by someone who wants to use me as a lab rat.
When there’s hope of a cure, I might change my mind.
And on that note;
Where would you start?
and how much would you need to research an actual cure
Have you even pondered this?
Does this ever invade your train of thought?
The only way to secure research funding for a cure is to use pharma money….
Quality
I believe where there’s a will, there’s a way …
Unfortunately , most translation drug research is completed by academic institutions who then sell or licence the molecule to pharma for further development, chiefly due to the costs and risks involved with bringing a drug to market. Look at Pfizer. I don’t think they’ve developed a new or novel drug in years. They simply buy out smaller companies with promising lead compounds.
Secondly, Pharma is focused on the bottom line. As a result we keep seeing the same drugs repackaged just enough to obtain a new patent ($$$). It’s a safer economic approach with a better chance of the drug being approved for use.
Obtaining research grants is a quagmire of gigantic proportions and typically the grant isn’t even enough to prove proof of concept in humans. A nationalised funding approach would fall apart because nobody could agree on the focus of research.
Our best chances are setting up a nexus between MS researchers and philanthropic organisations where research priorities are determined and funded (look at Medicines for Malaria. They have a similar model). Unlike the current MS Research charities, staff wouldn’t be paid eye watering salaries. The money would be pent on the actual research.
Pharma will never find a cure for MS. It will come via dedicated academics with the funding they need.
Most academics are business naive and sell their stuff to pharma for peanuts and so it is cheaper to buy stuff in rather than to make stuff, so pharma canned their R &D departments
It is worrying the way so many clinics have shut and are seeing no patients. A lot of people are beginning to question why the NHS continues to be in hibernation for all but COVID19 cases which it sometimes seems are batted away unless falling within certain criteria. And yet we know there are plenty NHS staff who like you want to keep providing the care and research they are so committed to. Your blog in itself is a huge help – even more so when we cannot see our own neurologists or have regular check ups and MRIs. Hopefully its existence can also draw attention to the fact that neurology treatment and research is suffering in the COVID era just as cancer related work is. Please do keep getting up and continuing to work on the task in hand … It is much appreciated and much needed in this stormy weather.
This calls to mind the serenity prayer The Don G (Prof G)
God, grant me the serenity to accept the things I cannot change,
courage to change the things I can,
and wisdom to know the difference.[1]
If I really thought about it though- (and i am after reading that)..,.I’d feel rather annoyed
MS has been around for ages; but as at today’s date; pharma will always be needed for research?!
Erm….so logically, they will never fund a study reasearch for a cure because, they’ll be halting a billion dollar industry?!
Durr…
So our incredibly hard working, intelligent, verbose, vibrant neurologists; are being funded to justify sledgehammers to crack nuts.
Those sledgehammers being loss of quality of life with ‘professional patient’ (which is a social impediment in itself) being your top achievement.
Show me an independent study that definitely evidences an improvement of quality of life at the 20year mark; following early ingestion of a dmd.
No ? Why? because there isn’t one.
Quality of life is the crux of it?! ….Isn’t it?!
I’d rather fully enjoy amazing experiences, with a wonky eye and a wobbly gait; a numb foot and a disposable catheter hidden in my knickers; without the millstone of medication dominating and defining my life and relationships.
So I’ll pay for it in five years?
Whose to say it wouldn’t happen anyway?
I’ve got better things to do with my time that being talked down to, patronised and pitied on a regular basis (neurologist ) by someone who wants to use me as a lab rat.
When there’s hope of a cure, I might change my mind.
And on that note;
Where would you start?
and how much would you need to research an actual cure
Have you even pondered this? Does this ever invade your train of thought?
The only way to secure research funding for a cure is to use pharma money….
Quality
I believe where there’s a will, there’s a way …
I was despondent about neuroprotective research before the pandemic. No change there.
Not all clinical trials have ceased. Many are recruiting in accordance with the FDA / EMA guidance on conducting trials during the COVID pandemic. Granted, most are industry sponsored so funding isn’t an issue. I’m managing 3 that are actively recruiting (In Australia). Sadly none in MS. The bigger issue is recruitment. Participants are less confident attending additional hospital appointments thereby increasing their exposure risk.
As outlined in other comments, perhaps now is the time to start focusing on translational research with the view of proposing new a novel treatments including neuroprotective agents whilst seeking the required money. Surely there are philanthropists that could be approached to secure funding for specific research that isn’t focused on immodulation.