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.