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.

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.


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

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. 

25 thoughts on “Do you have progressive MS; is your MS salvageable?”

  1. As an almost 70-year-old female with 30 years of MS, transitioning 3 years ago to SPMS, I am depressed and angered by what I perceive to be medical bias towards treating and testing newer, younger, more recently diagnosed PwMS. I try to stay up with research (thanx, Dr. G!) but recommendations for stopping treatment for people in my condition are maddening. I am not that affected outwardly, but the inward toll on my energy, mood, and endurance is sometimes overwhelming.

    1. Yes, the meta-analysis from the NIH showing that DMTs don’t work past the age of 54 years of age is all based on relatively short studies (2-3 years in duration) using the EDSS as an outcome. We all know that the EDSS is essentially a lower limb scale up to EDSS 7.0. Therefore, none of these trials took into account therapeutic lag and upper limb function which is why this paper is so damaging to the field of MS and has contributed to putting back thinking for decades.

  2. The patient case study is interesting. I was offered IfB in France 17 years ago after a gadolinium enhanced MRI. I declined. Even so, knowing now they’re less efficacious than the infusibles, the patient must have felt abandoned. Even if their efficiency` wanes with patients with this disease course, it is an anomalous way of treating people. In legal matters, if new legislation is enacted, people aren’t usually penalised retrospectively i.e. if they drive diesels exempt from road tax or run gas boilers. I’m guilty on both counts. The patient ought to be entitled to some sort of continuing treatment notwithstanding age or EDSS, without HCPs having to resort to creative use of other treatments that fall outside of more Stalinist NHS protocols.

    1. Dear Kit
      It was last year you were doing your bit to help us out. The work has been published in Anals of Neurology…”Work performed as part of this study at QMUL is funded by Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA with additional support from the MS community via crowdfunding”.

      Thanks for you effort and I hope that your have got a snorkel so that when you are swimming round the “Isle of Shite” (Thanks to our Government a load of shameful MPs and inept management by our water companies) you are not taking in too much raw sewage:-(

      1. Thank you for this link MD. I ‘ve just resumed sea swimming after lazily using my neighbour’s pool, because my beautiful zawn (teeny tiny beach) was invaded by visitors. I am triple vaccinated now and they have mostly gone home. Mercifully it is less polluted than my closer beach, with run off and worse. That said, the current débàcle around sewage dumping makes me sad, but not astonished by the venality of a governmnent talking themselves up, while thinking we actually believe them. As if..
        I really appreciate all the invaluable information in your blogs even they aren’t always relevant (I’m not on any meds). I have learned so much from them. Planning to reprise my 10x10x10 swims for the local park this winter, starting in 24 days time and trying to stick to the same 31 days, though with tide and wind in mind!

      2. Dont know how you cope with all the visitors…I came to enjoy the Cornish Summer…I mean rain; COVID fest from the Brits on tour, endless traffic jams and swimming on my favourite UK beach…My nads have yet to drop.., and the pub with the Best name “Bucket of Blood”

  3. I’m not a fan of awards. Find the Oscars cringe-worthy. I also don’t like scientific awards in areas where there have not been life changing discoveries / breakthroughs. Featured this week on the MS Trust website is a woman in her mid-30s who was diagnosed at 15. She is a full time wheelchair user and has advanced disability. The story is heart wrenching as she questions whether she should try for a family. I’m sure this sort of story isn’t unique. What a disconnect from conferences such as ECTRIMS and ACTRIMS where there is much back slapping and the giving out of awards for services to MS research. How can any researcher who spends a career in MS research be given any award. We still don’t know the cause of the disease or the drivers of tissue damage. There are still no therapies for neuro-protection, remyelination or repair. The best being offered for those who use a wheelchair is a slowing down of loss of function for the upper limbs ie you can brush your teeth for another six months! As we approach 2022 I find this situation almost impossible to believe.

    I admire all the efforts being made by Team G for those with advanced MS. However, no one really understands what this disease is about. Shutting down relapses isn’t going to be enough. Obliterating an MSer’s B cells won’t be enough. In 20 years time someone will work out that there’s a chronic viral infection (EBV) in the brain and the immune system is just doing what it is designed to do. The researcher who proves this and designs an effective therapy will actually deserve an award. Unfortunately in 20 years time most of us will be pushing up daisies or waiting for our bed bath in the care home.

      1. “This.”
        “I’m not a fan of awards. Find the Oscars cringe-worthy. I also don’t like scientific awards in areas where there have not been life changing discoveries breakthroughs.”
        Yes..this is incredible post.

      2. ANON, I thoroughly agree with you!

        This is a kind of Club of “experts” who are self-congratulatory, it is a very closed circle that does not admit their powerlessness to find DMTs.

        In France, where basic research is done, it is not considered to be a good idea to search DMTs that cure.

        Hospitals also advertise on private radio station(s) to claim legacies for the elderly. I let you imagine what you want to do with this money.

        You can look at for their gratuities for conferences, meals, trips, hotel nights offered by laboratories.

        With linux, it is enough to search with some commands to filter the benefits of each practitioner by his RRPS number: grep ‘RPPS;’ *csv > result.doc


      3. Hospitals also advertise on private radio station(s) to claim legacies FROM the elderly.

  4. If ever there was evidence of the potential for extreme damage as a result of the word ‘probably’ So very often assumed to mean ‘definitely’
    Why did Prof Thompson have to make what sounds like an unequivocal statement and instead acknowledge this is his view and is not held universally? Why not acknowledge the work being done to further understanding of the true extend of the therapeutic window in MS.

    I join Laura in being angry and frustrated, especially as, unlike as with Gerald Ratner, saying this won’t come back to haunt ProfT or those neuros who maintain his stance, but of course all the damage lands on PwMS!

    As I’ve mentioned before I was lucky enough to have a neuro who endorsed my receiving Alem age 51. Six years later and a mere three months ago my MS nurse said to me ‘I think your MS has been very kind to you’
    Kind? Or the impact of receiving Alem whilst still treatment naive – as you could then.

    As with Laura I try and stay on top of what is happening in the world of MS and utilise what I have learned – use of IF etc. How are others supposed to stay positive, motivated and hopeful when treatment doors are shut in their faces?

  5. Maddening how we have to advocate and act for ourselves with this disease, and are simply unable to trust the advice of neurologists. It’s hard for me to blame all the MS patients being hoodwinked by people selling diet and supplement cures when the actual medical profession puts people like Professor Thompson on a pedestal.

  6. Well said to all the previous comments here. Surely the time has come for PwMS and others in the community to become more vociferous/militant?

    1. I try to contact researchers in France, they do not want to answer to the plebs. A PwMS is a number in the herd.

      Apart from their daily activity, I have not detected any curiosity to discuss other subjects.

      But for their career, they are very active and very reactive.

      Charity business is the same.

  7. 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?

    What is the value of a decision that is not evidence based?
    If we say that this or that compound should not be taken autonomously by pwMS because not evidence based that they are safe and they work why we take pwMS off DMTs if we know that there is lack the evidence that this is safe and it makes no difference on the disease? Ethics says that decisions should stick to evidences… so?

    Also the post discusses about DMTs and progressive forms. I remember I read on this blog that long-term follow-up of the participants with PPMS to the first interferon trial made evident that they had slower progression observed many years later… so if I got it well we already have evidences that DMTs do positively influence progressive forms while discontinuing has negative influence.

    We already got the evidences, it is time to start doing. A meta analysis or a big review paper on this topic may help fix the bias some papers introduced? Or pwMS should wait for chariotMS to get to the conclusion?

  8. “Things have come a long way for people with progressive MS in the last 40 years.”

    Have they really Prof G? For those with progressive MS it’s a downward spiral of steady accumulating disability. While therapies have advanced to stop relapses, what real progress has been made for those diagnosed with PPMS? The therapies approved to date only address focal inflammation and not neuro-degeneration. Too many MSers in the prime of life are having to use wheelchairs and other walking aids. Too many MSers are leaving employment and seeing their lives becoming more and more restricted. I don’t know Prof Thompson but his views on what can be done for progressive MSers (ie not much) is another blow. The case below shows how dreadful MS can be ie death is seen as a better option. Still so much more to do to stop this disease ie stop progression not just slow it down.

  9. I too don’t like what the doctor said, or any of this for that matter, because now too, I am a person experimenting with no treatment after 25 successful years of Betaseron (Interferon 1B in the US). However, one can offer a “what if” explanation to the doctor’s comment- Since the beginning of injectables and ever since, there are a large percent (I’ll guess at 40 – 50%) who do not receive treatment right away. I still see them all the time. Perhaps the doctor is trying to motivate with a bleak opinion.

  10. Got PP MS and EDSS=6.5.

    Would have been better rewarding to find DMT that successfully addresses the causes of MS, rather than chattering and drawing personal conclusions after an ultimately unsuccessful career. Facts speak by themselves.

  11. Yes I have MS. PPMS.

    No I’m not running the gauntlet of DMT side effects for a slight, if any improvement of outcome.

    I have no interest whatsoever in helping fund those who insist on sticking to barking up the same old money trees.

    I have much more productive things to do, channel my precious energies towards.

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