Moving the goalposts

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

19 thoughts on “Moving the goalposts”

  1. Prof G,
    Thanks for this reminder. I’ve never smoked or drunk alcohol (occasional sip of champagne at a wedding), have been on Keto for 7 months and lost 30 lb (so my weight is in the healthy range), my blood pressure is 95/65 (I’m mid 50s), and I exercise every day for one hour (walking the dog through woods and cycling). I take 10,000iu of Vit D and 1200mg of Alpha Lipoic Acid daily. I sleep very soundly c. 7 hours each night. Thankfully, I have a fairly large family and a good group of friends. I’m a big reader (mostly non-fiction). I totally support the idea of self-management and taking responsibility for your own health.
    However, despite all my efforts, the thing that keeps me awake at night (for a little bit) is “smouldering MS”. I thought I’d dealt with the disease c.15 years ago with an IRT, so it was a shocker some c.13 years later to find out that shutting down the relapses may have little long term benefit as they are not the real disease!
    You say in your post that “This is why we now have to develop treatments that slow or stop the accelerated end-organ damage that defines smouldering MS.” When you have some time, could you do a post on what promising drugs are in trial / in the pipeline to try and slow or stop smouldering MS, and how the success of these drugs will be measured. I recall that you did a post on the numerous processes that may be involved in driving smouldering MS. My worry is that the numerous processes will require numerous therapies to address them and I can’t see any trials being launched which combines 3 or 4 therapies, when getting a trial launched to test a combo of two therapies appears to be near impossible.

    1. Hello Sid, the smouldering keeps me up at night as well. Not only the smouldering but also the fact that one could become SPMS because of the smouldering and being denied the access to some DMDs. I don’t like drugs interfering with lymphocytes trafficking. But there are therapies that may aim at the smouldering MS: BTKi for the pharma side or the SIZOMUS trial where the proteasome inhibitor will be given on top of a DMD (more or less, look at the trial data).
      Personally, I believe that this wave of drugs could be a good one for us. The pharma pack has proteasome inhibitors trialled for other autoimmune diseases (see KZR-616) and if only one is proven good for MS the pack will start hunting.
      Since I wrote about my favourite study I report this paper for the BartsMS team. Ixazomib human data in case you missed it!po=1.28205
      PS I could not send a message with the link via the Menu -> about -> Ask -> barts-ms it returned an error

    2. ” I thought I’d dealt with the disease c.15 years ago with an IRT, “………………………..Did you have alemtuzumab..? If you have had little brain loss in these last 15 years….you aren’t smoldering.

  2. 650m is awesome Prof G. The naysayers should bow their heads or hold their tongues, or both. You are a driven man. What does your orthopaedic team have to say? Keep posting about your recovery path. It is abslolutly not boring and might take pwMS’ minds off their own travails.
    It also helps with a sort of mental to healing for for pwMS, to focus their love and hope towards others who are ill. Like being pleased instead of envious when when another person does well, it soothes the psyche in MS that contributes to a better disease course. My theory: works for me.

  3. “Barts-MS have started investigating ways of helping our patients expand their social networks as a treatment strategy for MS.”
    That would not work with me. I look to medical professionals to help with my MS (actually only physiotherapy), but they should all stay out of my personal life.
    (I’m not a patient of yours, you’ll be glad to hear. 🙂)

    1. These initiatives are not led by us but by people with MS. We access them via social prescribing routes. However with budget constraints about to get tighter I wouldn’t be surprised if the NHS pulls its social prescribing budget.

      1. Personally I would welcome ideas for establishing a wider social life. I was doing ok before covid, I enjoyed what I had but am now finding the lack of socialising uncomfortable. I am lucky to have my husband at home every day which is nice but it’s because he has been made redundant so that has brought new issues to deal with. Covid is causing havoc in so many ways 🙁

      2. Reminds me of the old “one man’s meat is another man’s poison”. Or woman’s, in my case. No doubt it’s good for some / many.

      3. Do NHS staff work with local governments?
        As many local governments offer free and low cost activities, such as cooking and healthy eating workshops, allotment and gardening groups & workshops, exercise groups and classes, free health walks, etc.

        Then there might be less need for social prescribing to come out of NHS funds, if they were to utilise these.

  4. Prof, can i just test my understanding of the smouldering MS / relapse theory. The real MS is end organ damage, driven from inside the CNS. The cause originates from outside the CNS but crosses the blood brain barrier. Relapses are essentially the immune response to what is going on within the CNS. If detected early enough, the immune response can be re-programmed / shut off (no more relapses). DMDs (bar maybe clad) do not penetrate the BBB so there is, in theory, a virus still lurking although without relapses and consistent penetration of the BBB, it can in some cases, fail to establish itself / get bored / die out. This is what has happened in the few cases that you considered to have been ‘cured’ by Lemtrada. However, where not detected and treated early, the real MS does establish itself. So we can turn off relapses through whatever mechanism we like – HSCT, Lemtrada, Ocrevus and this will provide some short to medium term relief for the patients but ultimately, the real MS will get us in the end? I am sure that there is some flawed logic here so please correct me where i have gone Wrong. As a follow up, is there anyway of a patient to know when they are ‘to late’ and the beast has already set up shop?

  5. Glad to hear you’re improving. I have followed your advice about a ketogenic diet and have noticed i no longer suffer the debilitating post-prandial fatigue. I also moved from being over my healthy BMI range to being bang in the middle of the range without even feeling hungry. When you say intermittent fasting do you mean fast for a day or 2 or for 16 hours daily? I have donated to your appeal, wish i could give more to a very relevant study.

    1. Thank you. I am sure what the best intermittent fasting protocol is. I have tried 5:2, 16:8 and 20:4 and they seem to be doable. Would need to study how good they are at stimulating ketosis. I think it finding out what is best for you. Jack Dorsey of Twitter does 22:2 which is brutal.

      1. Hey Prof G ,
        Hope the recovery is going well.
        if you think Jack’s protocol is brutal, have you ever followed Dr Petter Attia? He like you is a super brain and very fascinating man. He studies longevity and really would recommend taking a listen to him.
        He does a 7 day fast every 90 days. Pretty insane as he still continues to train.
        here is a link which he has more achievable protocols.

  6. A very interesting post (as usual), especially as you are laid up. The smouldering MS idea makes alot of sense to me and, three years since diagnosis, I am learning more about my MS and how to manage it. Having had 2 rounds of Lemtrada and NEDA, my MS team are not really interested in my renewed symptoms. I am aware that they are far less severe since treatment, and I am hoping that this lasts. For me, exercise is key, and I do believe that if I stopped walking my 2 miles every day, I would lose my mobility. Keeping positive and keeping moving are very closely linked, I think.

  7. Prof G,

    I read you write about “to consider HRT (hormone replacement therapy)”. I used the search function of this forum to deepdive into this subject. It’s all about menopause and such.
    Are the also suggestions on HRT for men?

  8. Metformin – Luis flagged up a few days ago under Nov Q&A on Medical Xpress, research that showed Metformin isn’t beneficial in the old compared to the young, who don’t have diabetes.
    Where will this sit in regards potential use of Metformin?

    1. Show me the paper please Luis…however one can argue that metformin is the switch factor but you need another agent to do the repair

Leave a Reply

%d bloggers like this: