Beyond NEDA

B

Prof G are we being lulled into a false sense of security by being told that we have no evident disease activity (NEDA)?

A patient of mine, who I have been looking after now for over 11 years, asked me in clinic a few weeks ago why despite being NEDA for 6 years, on a highly effective maintenance DMT (fingolimod), has she gone from being able to run 5-10 km to needing a stick and barely managing to walk from the Whitechapel Underground Station to my clinic (~200m), without having to stop and rest?

What this patient doesn’t know, despite no new visible T2 lesions, is that she has developed obvious, to the naked eye, progressive brain atrophy.  This particular patient prompted me to write a few blog posts to try and explain what is happening to her brain. Before reading the remainder of this post you may want to read the following posts:

An important question in relation to this patient is why do some DMTs have such a profound impact on end-organ damage markers, in particular, brain volume loss and others do not? Not all DMTs are made equal when it comes to preventing, or slowing down, brain volume loss.

At the top of the league table are alemtuzumab and HSCT (~0.2-0.25% loss per annum). Both these treatments are NIRTs (non-selective immune reconstitution therapies). Natalizumab is next with an annual brain volume loss in region of 0.25-0.30% per annum. Ocrelizumab (anti-CD20) comes fourth with a rate of brain volume loss of ~0.30-0.35% per annum. Fingolimod 5th at ~0.4% per annum. Cladribine has a rate of loss of brain volume of ~0.55% per annum with the other runs after that.

For me, the disappointment are the anti-B cell therapies, ocrelizumab and cladribine. Despite these DMTs being very effective at switching off new focal inflammatory lesions (relapses and new T2 and Gd-enhancing lesions) their impact on end-organ damage is only moderate. These observations have convinced me more than ever that focal inflammation is not MS, but simply the immune system’s response to what is causing MS. The latter hypothesis is what I have been presenting as part of my ‘Field Hypothesis’ for several years on this blog.

What these observations are telling me is that peripheral B-cells are a very important part of the immune response to the cause of MS, but they are not necessarily involved in driving the true pathology, which is causing the progressive brain volume loss. The caveat to this is that anti-CD20 therapies and cladribine may not be eliminating the B-cells and plasma cells within the CNS, which is why we need add-on treatments to try and scrub the brain free of these cells to see if the brain atrophy rate ‘normalises’. This is why we are starting a safety study this year of an add-on myeloma drug to target the CNS B-cell and plasma cell response to test this hypothesis.

What does this mean for the average person with MS? Firstly, you may not want to dismiss alemtuzumab and HSCT as a treatment option. These NIRTS differ from anti-CD20 therapies and cladribine in that they target both B and T cells. We may need to target both these cells types to really get on top of MS. I am aware of the appeal of anti-CD20 therapies and cladribine; they are safer and easier to use because of less monitoring, however, this may come at a cost in the long-term. The SIRTs (selective IRTs) may not be as good as the NEDA data suggests. Please remember that once you have lost brain you can’t get it back.

The tradeoff with alemtuzumab and HSCT is the frontloading of risk to get the greatest efficacy over time. Choosing a DMT on a rung or two down on the therapeutic ladder gives you better short-term safety and makes the lives of your MS team easier, because of less monitoring, but at a potential long-term cost to your brain and spinal cord.  This is why to make an informed decision about which DMT you choose is a very complicated process and subject to subtle and often hidden effects of cognitive biases. The one bias I am very aware of is the ‘Gambler’s Dilemma’, be careful not to be lulled into a false sense of security by your beliefs; most gamblers lose.

Over the last few years you may have seen a theme developing in my thinking as we move the goalposts in terms of our treatment target beyond NEDA-3 to target end-organ damage, i.e. brain volume loss, T1 black holes, the slowly expanding lesions (SELs), neurofilament levels, cognition, sickness behaviour, OCBs, etc. Our treatment aim should be to ‘Maximise Brain Health’ across your life and not just the next decade. Please stop and think!

When I was preparing this post I dropped Prof. Doug Arnold an email about the impact of alemtuzumab and HSCT on the slowly expanding lesion or SEL. Unfortunately, these analyses have not been done despite good trial data sets being available for analysis. He said it was a resource issue; i.e. a euphemism for money and permission to do the analyses. For me, these questions are the most important ones to answer in 2019. Wouldn’t you want to know if alemtuzumab and HSCT were able to switch off those destructive SELs in your brain? Knowing this may impact your decision to go for the most effective DMTs; frontloading risk to maximise outcomes in the long term.

What should I advise my patient; to stay on fingolimod or to escalate to a more effective DMT?

The following articles are the important ones for you to read or at least be aware of:

Article 1

Lee et al. Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis. Mult Scler. 2017 Mar;23(3):420-431.

BACKGROUND:  A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy.

OBJECTIVE: We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT.

METHODS: Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions.

RESULTS: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was -0.23% per year, consistent with the rate expected from normal aging.

CONCLUSION: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.

Article 2

Arnold et al. Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS. Neurology. 2016 Oct 4;87(14):1464-1472.Neurology. 2016 Oct 4;87(14):1464-1472.

OBJECTIVE: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).

METHODS: The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II).

RESULTS: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a.

CONCLUSIONS: Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS.

CLINICALTRIALSGOV IDENTIFIER: NCT00530348 and NCT00548405.

CLASSIFICATION OF EVIDENCE: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.

Article 3

Vavasour et al. A 24-month advanced magnetic resonance imaging study of multiple sclerosis patients treated with alemtuzumab. Mult Scler. 2018 Apr 1:1352458518770085. doi: 10.1177/1352458518770085.

BACKGROUND: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment.

OBJECTIVE: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab.

METHODS: A total of 42 relapsing-remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated.

RESULTS: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year.

CONCLUSION: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

77 comments

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    • Not at all. It is all about benefits and risks and individualised decision-making. What is clear we need to get serial end-organ damage markers into the clinic ASAP to help inform decision making. Who knows maybe cognitive testing may be the way to go. A lot of atrophy is occurring in the gray matter and this could be more sensitive to change.

      • The reality, as I understand it ProfG, is that there’s little provision or opportunity for ‘individualised decision making’ regrettably. For example:
        Multiple Sclerosis Treatment NHS about Fingolimod states ‘ maybe offered (not even Will Be) if you have RRMS and experience an increase number of relapses despite treatment with other medicines such as beta interferons’

        Treatment Algorithm for Multiple Sclerosis DMTS NHS England 2018 states under General principals of Drug Switching: 1. Intolerance 2. Disease activity, but only if there’s been adequate exposure and with good adherence to a DMT.

        So the escalation process is enshrined in the NHS protocols and not everything can be laid at the door of dinosaur neuros or the extent to which individual patients maybe risk adverse.

        What approaches or strategies can patients utilise to best facilitate their access to secondline therapies via their local NHS providers?

        How much wiggle room is there in terms of circumnavigating the eligibility criteria?

        Picking up on your subsequent point about smoking I’m hoping that future posts, such as your planned one on diet, will focus on what, if anything, we can do as PwMS to maintain our own brain volume/health.

        There’s the regular mention of lipoic acid on the Blog and information on anything like this that we can do/use that’s of potential benefit will be very helpful

        I’m hoping the intense focus dementia is currently receiving will prove of benefit to those of us with neurodegenerative conditions and any related research such as that I heard mentioned on radio 4 of a current study looking at the transfer capacity of online cognitive
        training. As the researcher said: becoming good at a game is one thing, having it apply beneficially to everyday life is something else again.

        Recognising that Alemtuzumab and HSCT will remain accessible here in the UK, to a limited number of patients, at least for the foreseeable future, then the Blog focussing on sharing other relevant research data on dementia etc and information on lifestyle etc may well be the most effective provision for the majority of PwMS.

      • Are there any statistics to show us how many folk with MS have actually gone on to develop early onset dementia before the age of 65? I guess time will tell if there is a considerable reduction in dementia cases due to the uptake of DMTs, particularly the most effective?

        • Most pwMS given sufficient time will develop cognitive impairment. To call it dementia it has to be progressive and impact on your ability to work and function in society. Therefore frank dementia is less common. However, as most neurologists don’t do routine cognitive testing I don’t know if we will get the answer to your question anytime soon. I will do a post on this topic in the next few days.

    • In the AFFIRM study, the brain volume loss on natalizumab was 0.24% in year 2. However, some real-life datasets are slightly worse than this. The problem with the real-life data is that most pwMS treated with natalizumab have highly active MS and come onto treatment with a lot of damage, which has to work its way through the system. There is not much between natalizumab and alemtuzumab when it comes to brain volume loss. Natalizumab at least provides a holding option that allows one to think about a long-term treatment strategy. The latter principle is what is underpinning our #AttackMS trial.

      • A costly holding option I reckon:
        1) an obvious cost in brain volume
        And 2) increase of ms activity free cessation making a therapeutic switch riskier the longer the wait is.

        Furthermore, what would someone reasonably switch to? Alemtuzumab shows moderate improvements with a heavy secondary autoimmunity price tag.

  • Prof G,

    Thanks for this post. DMTs have only been around for some 25 years so users of them are really guinea pigs in terms of showing what the long term outcomes are. It didn’t seem that long ago that the B cell depleters were going to take over the world as the go to treatment for MS, but there seems to be a shift (given their impact on brain volume loss). A friend also did well on fingolimod (in terms of relapses), but slowly progressed. Given the emerging data / information relating to brain volume loss shouldn’t you (neurologists) be giving patients a stronger steer to treatments such as Alemtuzumab and HSCT? An easy to swallow pill or under the skin injection, with minimal follow-up monitoring, is an attractive option, but comes with the high likelihood of disability down the line. The secondary autoimmunities with Alemtuzumab are like the backstop with the Brexit withdrawal agreement. If you could get rid (or reduce) the secondary autoimmunities, Alemtuzumab would be accepted by most as the sensible way forward.

    • Freddy it is all about having information at hand and choice. The problem with NIRTs is that are not often on the table when it comes to choosing.

  • Thanks Prof G. Great article and makes total sense both scientifically and fits the data from real life experiences. I for one new Alemtuzumab was the option for me before the data on brain atrophy. From reports patients making miracle recoveries after the drug that wasn’t seen in any other treatment aprt from HSCT. Also I believed if someone is stealing your crown jewels (brain and spinal volume loss). Should you really be worried about petty cash going missing from the till? (2nd autoimmunity)

    • The secondary autoimmune risks are not that petty; some people have died as a result. The great tragedy for me is that I am sure we can derisk the autoimmune events, but Genzyme was not prepared to take on the challenge when we put forward 5+ years ago what we thought then was the optimal study design.

      • I think we now need to compare HSCT to alemtuzumab to see which one comes out on top in terms of efficacy and safety. If HSCT wins then we are going to have to upscale our HSCT units to cope with the avalanche. We would also have to consider offering HSCT first-line.

        • Until neurologists can give a better prognosis then I would imagine many people with MS would be very hesitant to take on board the very serious and potentially deadly side effects of these potent treatments. And more problems seem to be emerging with Alemtuzumab as time goes on. Can we be confident at this stage that it will not ultimately have the same disappointing results as Rituximab after 10 plus years? As you have previously commented on this blog:“…… my initial enthusiasm for ocrelizumab has been dampened by Steve Hauser’s comments that a large number of their patients with relapsing MS who have been treated for 10+ years on rituximab have now developed SPMS. If this is correct then anti-CD20 B-cell depletion will not be a panacea. ”
          Would you consider Natalizumab to be perhaps a considerably safer option as long as one is JCV negative?

      • Yes your right Prof G. That’s why taking baby asprin. And going to ask my neuro for maintenance therapy such as abugio if I paid for it. But still most 2nd autoimmunity is thyroid related. Some being deadlier than MS.

    • I’m an alemtuzumab patient who got very unlucky with the secondary autoimmunities. I’ve had severe ITP multiple times to the point that I’ve needed rituximab and other high cost drugs, severe Graves’ disease requiring a thyroidectomy, and severe autoimmune haeamolytic anaemia requiring more rituximab. All of these required a fair amount of time critically ill in hospital and a lot of drugs that were high cost, some of which I had to self-fund because our health system doesn’t use them for those particular indications. Basically I started as a neurology patient and then have ended up with a team of haematologists nursing me through.

      On the flip side it’s controlled the MS well and in all likelihood we will get past this with no long term damage done. But regardless these side effects need to be better managed, it’s not always as simple as steroids + time. If you get unlucky you’ll need a good team around you. I wonder what would have happened if I’d had rituximab 6 months after my infusion rather than after the secondary autoimmunities appeared.

      • Yes I agree. These risks can be eliminated if it weren’t for the self interests of big pharma. Sorry to hear of your experience. That’s why prempting the risks. Also going to India to self fund Rituximab. Barts should take. Lead on this and make it rule to treat sll lemtrada patients with Ocrelizumab after 6 months of the last dose of alemtuzumab

        • It needs to be evidence based.
          On what basis do you select a 6 month dosing schedule?
          One could easily justify a different time our.

          I think that previous treatment with alemtuzumab may give probems of ocrelizumab based on NHS englands rules..The neuros can correct me on this one.

          • Granted hard evidence is a great idea, but in the meantime patients like me are being exposed to critical side effect risks. There is a whole branch of medicine (haematology) with experience using these drugs for other indications and they’ve seen these effects before, seems silly not to draw on their expertise. It’s perhaps more art than science at times, but you have to start somewhere.

            I picked 6 months because any closer seems pointless given the effect of alemtuzumab on both the T and B cells, and the relatively long term suppression effect that rituximab has on B cell numbers. But perhaps monitoring of lymphocyte subsets is a better way to do it. After I had alemtuzumab my absolute lymphocyte count was back in the normal range after one month (subsets were not looked at), but 2-3 years down the track my T cells were still creeping back into the normal range particularly in terms of the ratio to B cells. So filling in the blanks as a lay person – I think it’s a reasonable assumption that my B cells rushed back too soon and that slowing this process down might head off the B cell autoimmunities. If we started doing a trial now we would have answers within a few years, pick a couple of timeframes and dosages based on the opinion of those with experience and go from there.

            On a related note I think the monitoring of side effects post alemtuzumab could be improved. Apart from the subsets there should be a procedure where more in depth tests get added on routinely so that practicioners can make actual decisions. For example – reticulocyte counts seem like a no brainer once someone has an abnormal red cell result. Knowing that haemaglobin is a little low is a start, but do you wait to see what happens next month, or next week, or the next day? I know from bitter experience that counts can shift VERY quickly. Looking at the retics etc gives important context that could save lives. I don’t see how the current setup supports best practice management.

  • Prof G,
    Very interesting post. I don’t know what to think. Scares me the feeling of calm not being calm at all. I have experienced the disappointment of fingolimod, good at the beginning but horribly wrong at the end . With Cladribine i am now again in a calm phase but scares me to think this could turn to the worse at anypoint, what can i do know? Just wait? I thought cladribine was going through BBB.

    • Cladribine gets through the blood-brain-barrier; CSF levels are ~25% of blood levels. However, we don’t know if this is sufficient to do the job. There is a hint that pwMS treated with cladribine may lose their OCBs, and by inference plasma cells, 10 or more years after treatment. We plan to study this. My biggest concern is that the level of T-cell depletion on cladribine, in the periphery, is too low to really get at the cause of MS. All this will come out in the wash with long-term studies. The problem for people with MS now is that time is brain and you don’t necessarily have the time to wait 15-20 years to get the answers.

      • “Cladribine gets through the blood-brain-barrier; CSF levels are ~25% of blood levels. However, we don’t know if this is sufficient to do the job. There is a hint that pwMS treated with cladribine may lose their OCBs, and by inference plasma cells, 10 or more years after treatment.”

        Weird thing is that it looks like Cladribine clears OCBs, and Alemtuzumab doesn’t? How come?

        Another question about depletion: with Cladribine, grade 3 or 4 lymphopenia is actually rare and it’s pretty common with Aletmtuzumab. So if someone under Cladribine depletes down to Alemtuzumab levels of depletion, Cladribine should get comparable outputs? Why wasn’t then the dosage of Cladribine chosen accordingly (with BARTs Cladribine protocol or after that MAvenclad with higher dosage tested?). Malignancy rates for Cladribine are actually lower than most high efficiency DMTs (I looked at the comparison graphs from your slides).

        Cumulative higher dosage for Cladribine is actually getting to patients via retreatments, if there is a disease reactivation. Could that explain cca >50% clearing of OCBs in patients with Cladribine?

        • The main CSF cladribine study was done after 10 years and ~50% of treated MSers had lost OCBs and did better. The alemtuzumab CSF study, which I was involved in, was done after only 3 years. Similarly, the HSCT CSF study done in Canada shows was also done early and has only a minority losing OCBs. I think the OCB question takes decades to read-out because plasma cells are so long lived. This is why we are targeting them using myeloma drugs to see if we can make them disappear sooner.

          • We will let you know as soon as we have all the approvals etc. in place. We don’t want to raise expectations if we can’t deliver the trial. We have the grant, however, to do the study.

        • Yes, we chose a relatively low dose of cladribine for safety reasons. I am sure if we used higher doses and took down more of the T-cell compartment we would get greater efficacy. Again it is all about benefits and risks. T-cell depletion comes with many more risks than B-cell depletion.

  • Very interested in your upcoming safety study using an add-on Myeloma drug. Will you be looking for patients currently taking Cladribine to enter a trial using this drug? If so, will this study only take place in London or would it be open to anyone in the UK to participate? Please keep us informed how we can take part! Perhaps you could post about this Myeloma drug when you have time and explain why you think it may help people with MS.
    Thankyou.

  • Please could you remind us of any previous posts about whether or not to use DMTs in people of older age?Would you say that the most potent treatments, Alemtuzumab and HSCT, are too much of a risk for patients beyond say 50 years of age, especially if their MS is slowly worsening with no relapses? Would it make sense for these particular patients to take a safer drug like Cladribine/Ocrelizumab?

    Also, do you have up to date info on how patients are doing long-term on Aubagio as I seem to remember you commenting in the past about positive experiences from some of your colleagues ??

  • Great post Prof.G,
    However I’m still not sure if we can directly compare the atrophy data since the patients baseline characteristics were very different between trials. For instance, in alemtuzumab CARE-MS I trial the patients had a mean EDSS of 2.0 and only 2 years of disease duration, while in the other end of the spectrum in cladribine trial patients had a baseline EDSS of 3 and 9 years of disease duration. In your opinion can these baseline differences influence the end atrophy results?

    • It may make a difference but the natalizumab and HSCT cohorts are older and more active. The MAGNIMS data also show that atrophy relative to brain size occurs at similar rates across the disease course from RIS to SPMS and PPMS. So I don’t buy this argument. If you have MS you wouldn’t you want to try and normalise your brain volume loss? Or not? At the end of the day you need to have this discussion with your HCP.

      • Did you you know smoking speeds up brain volume loss? Despite telling this to many of my patients who smoke their success rate in stopping smoking or switching to e-cigarettes is depressingly poor. So why should knowing the relative impact of DMTs on brain volume loss over and above NEDA affect your DMT choice?

  • Immune reconstitution seems the easiest way out from the disease -still not easy. This is great news for MS. The only downside is that we might never learn what is happening and people develop MS. Only a vague and unproved EBV.

  • Prof G
    Your post has many rates of atrophy under different treatments. Can you point to another one of your blog posts that talks about the original publications, or can you tell us which trials/publications so we can read about the study designs? Like AFFIRM you mentioned for natalizumab.

    • Will do, but this will take time and effort. I have posted the alemtuzumab and HSCT data in the post. The ocrelizumab data is the OPERA publications and the Arnold poster that is online from ECTRIMS 2018. The cladribine data is published and I am a co-author on this.

      Any volunteers who want to help me do a brain atrophy meta-analysis of the DMTs including HSCT?

      • If you have doubts about going beyond NEDA and targeting brain atrophy you should read this paper. What I am saying is old news. I am surprised that many of you are unaware of the importance of end-organ damage in MS and its role in long-term outcomes.

        Sormani et al. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol. 2014 Jan;75(1):43-9.

        OBJECTIVE: To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing-remitting multiple sclerosis (RRMS).

        METHODS: We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression.

        RESULTS: Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R(2)  = 0.48, p = 0.001) and on active MRI lesions (R(2)  = 0.61, p <  0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R(2)  = 0.75, p < 0.001), and both variables were retained as independently related to the treatment effect on disability progression. INTERPRETATION: In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the 2 MRI measures predict the treatment effect on disability more closely when used in combination.

        • In response to your comment: “I am surprised that many of you are unaware of the importance of end-organ damage in MS and its role in long-term outcomes.” When I was given my diagnosis four years ago, no real explanation was given to me about multiple sclerosis, no information to take home and read. Simply advice to start taking Copaxone. I can honestly say that it’s only through discovering the Barts blog (alongside the MS Trust and MS Society) that I have found the information I’ve desperately needed so a big thank you to all your team. I consequently requested a referral to a MS specialist neurologist who is much more proactive regarding treatments and giving advice.

  • A new research drug in phase 1 clinical trial has incredible breakthrough in Mnd. Leading to 70% reduction in progression. Could copper deficiency be the reason behind progressive MS? And treatments like HSCT and Lemtuzumab add copper back via cell destruction?

  • Amazing post. As a patient who has been on Tysabri for 13 years and seems stable do I ask my neurologist if we are measuring brain volume loss every 4 months when I have an MRI? I read all of my reports and do to remember that verbiage. For those of us that have been on highly effective DMT from the start and are older now how do we approach the HSCT conversation?

  • Speaking of add on therapy, Lipoic Acid as a supplement was suggested to reduce brain volume loss in SPMS in a phase II random trial vs. placebo. Spain R…Bourdette D “Lipoic acid in secondary progressive MS” Neurology: Neuroimmunology and NeuroInflammation, 2017 Vol 4. 1200 mg of racemic LA daily over 2 years lead to brain loss of 0.21 vs 0.65 for placebo (p=0.002; 27 vs 24 patients). They had some improvements in walking but wasn’t significant, and the T2 lesion volume trended towards larger in the lipoic acid group, but again that wasn’t significant (was that because there was more volume in the LA group?).

    Possible an add on therapy supplementing a B cell depletor with LA may work if the depletor stops lesions, while the LA stops volume loss.

    Any comments?

  • Brilliant article Prof. G – many thanks for your efforts.
    Can we know a little more about when you say “The caveat to this is that anti-CD20 therapies and cladribine may not be eliminating the B-cells and plasma cells within the CNS, which is why we need add-on treatments to try and scrub the brain free of these cells to see if the brain atrophy rate ‘normalises’. This is why we are starting a safety study this year of an add-on myeloma drug to target the CNS B-cell and plasma cell response to test this hypothesis.”

    I’m currently on Cladribine and would like to know a bit more so I can discuss this with my consultant at oour next meeting – sounds like something I should be considering. That or maybe seeing if i can move onto Ocrelizumab [if (1) i can actually get it, and (2) am eligible for it after Cladribine]. With EDSS of 6.5 the options are limited.

    Thanks,

  • Prof G this post is very in line with a comment you made after ECTRIMS way back in 2015, which I won’t forget:

    “However, my initial enthusiasm for ocrelizumab has been dampened by Steve Hauser’s comments that a large number of their patients with relapsing MS who have been treated for 10+ years on rituximab have now developed SPMS. If this is correct then anti-CD20 B-cell depletion will not be a panacea. ”

    https://multiple-sclerosis-research.org/2015/10/clinicspeak-highlights-and-hot-topics-lecture-at-ectrims/

    • This time patients were ahead of scientists when they were heading abroad for HSCT to STOP progression, an incomprehensible term for them. Since Ocrevus could totally control inflammation why do harsh chemotherapy (this was the state of mind in this blog too and for some members of the team anti-cd20s are still the Holy Grail of MS).
      The problem is not so much the lack of knowledge and the dinosaur attitudes as is the distance between the life of an MS patient and his/her doctor.
      #ThinkProgressive-ly

      • I don’t think patients were ahead of the scientists. Scientists showed that BMT was a very successful treatment for autoimmunity in animals and patients long before it was tried in MS. I do, however, think you were ahead of the vast majority of neurologists. A say majority as some innovators provided the proof of principle that BMT and, subsequently, HSCT works and works exceptionally well.

  • Thank you Dr. G for this honest post. This post is frankly depressing, as are most of the posts in the stagnant MS research world. I believe this is the 10th year this website has been open and we are no further ahead progressive MS with zero add on therapies that you have called for repeatedly in your treatment pyramid.

    It shows that there is almost a complete uncoupling of neuro-inflammation and neuro-degeneration. We are nowhere near stopping or treating progressive MS successfully in the imminent future.

    Treating neuro-inflammation with B-cells and T-cells inhibition is obviously just treating a downstream process or reaction to the real disease which is taking place, as you say, in the “field effect” area.

    The focus on inflammatory DMD treatments only approach for monetary purposes and ignoring meaningful neuro-protectants, remyelination and neuro-restoration add on therapies for the last 1/4 century is pathetic.

    I really need to stop reading MS research and stop hoping for something that will help stop progression and restore function as this is an unrealistic reality.

  • 40 comments on the first day!
    Did I not say that this is the holly grail for many of the blog followers.
    I still believe that the blog deserves a whole section (menu entry) along the lines of “NERA 3 to NEDA 4 “. It is as valuable as the “I’ve just been diagnosed section” in my view, an no MS blog or charity is spending enough time on this matter.

    Tony

  • ECTRIMS 2018. P588 – Long-term reduction in brain MRI disease activity and atrophy after 5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis. D.L. Arnold, L. Kappos, S.L. Hauser, X. Montalban, A. Traboulsee, J.S. Wolinsky, M. Manfrini, V. Levesque, P. Villoslada, S. Belachew, F. Model, S. Hubeaux, A. Bar-Or

    Background: The efficacy and safety of ocrelizumab (OCR) in relapsing multiple sclerosis (RMS) were demonstrated in the 96-week double-blind control period (DBP) of OPERA I and OPERA II (NCT01247324; NCT01412333). Long-term brain tissue preservation is a critical objective in the treatment of multiple sclerosis (MS).
    Objective: To assess brain MRI measures of disease activity and atrophy after earlier vs delayed initiation of OCR at 5 years from core study baseline in Phase III trials in RMS.
    Methods: At end of DBP (Year 2), patients entered the open-label extension (OLE) and continued OCR (OCR-OCR) or were switched from interferon (IFN) β1a to OCR (IFN-OCR) and were analysed until Year 5.
    Results: Earlier OCR-treated patients (5 years of OCR) vs delayed IFN-OCR switchers (3 years of OCR) had lower brain atrophy from core study baseline to the end of Years 3, 4 and 5 measured by WBV change (-1.31%/-1.51%, -1.58%/-1.87% and -1.87%/-2.15%; p< 0.01 for all)

    Therefore, does this mean, people on continuous ocrelizumab had annual whole brain volume loss between year 3-4 = -0.27% and year 4-5 year -0.29%. Those started after 2 years had -0.36% brain volume loss year 1-2 on ocrelizumab and -0.28% year 2-3. In the HSCT paper it took time to to slow atrophy.

    • Yes, that is right. This is therapeutic lag. The same thing was seen with HSCT, alemtuzumab and natalizumab. It takes time for the damage to work through the system.

  • Prof. G, to indirectly find the rate of brain atrophy, EEGs may be helpful, especially sleep EEG recordings. You will probably see a slowing of EEGs, perturbations in EEG synchrony or connectivity, and reduction of EEG complexity. Note that ERPs might not be very useful. MEGs have some advantages over EEGs for such applications. But as you know, they are not affordable. Gait dynamics could be informative as well.

  • Prof G if I go onto say ocrelizumab can I then switch if my brain volume loss is say excessive several years down the line? Or to start and add-on treatment as they emerge in the future?

    • Unfortunately, it is difficult to implement brain volume measurements at an individual patient level because the measurement error is too large. However, a large change over several years is more meaningful and could trigger some decision. Please note we don’t have an evidence base that switching because of brain volume loss will be effective, i.e. if your NEDA with lets sat 1.8% BVL over 2 years will moving upwards work? I am not sure.

    • Yes, it does. Cladribine works and has CNS penetration and has an impact on endorgan damage, however, it does not appear to be as effective as HSCT and akemtuzumab in early RRMS. We also have to be pragmatic, people with more advanced MS will not tolerate treatment with alemtuzumab or HSCT very well and the monitoring requirements are very arduous . Need to realise that at the moment these pwMS have no treatment. I do think the B-cell therapies will make very good maintenance treatments and platforms to add-on other DMTs. There is also pilot data from our unit and others that there is a good chance of cladribine being effective in more advanced MS. Please note the aim of this treatment is to protect, or slow down loss, of upper limb and hand function.

      • Thanks for the response
        Prescribing criteria aside why would alemtuzumab be considered too arduous for people with more significant disability?
        Regarding monitoring the monthly blood and urine tests are easy enough to administer especially when they can be done locally.
        Regarding the potential post treatment problems the most common is definitely thyroid which in the scheme of things when you have MS is actually not that big a deal.
        I understand that hsct is a brutal treatment but alemtuzumab not so much.

    • It is simply not feasible to treat all people with active MS with a NIRT. This post is simply to make you aware that on average people treated with HSCT and Alemtuzumab will do better when it comes to brain volume loss. You have to realise that hidden in the data sets of the other DMTs are responders and non-responders and the responders can do as well as those treated with HSCT. The problem we have is identifying the responders up front.

      • As a recipient of Alemtuzumab this post has really hurt me for those who can’t be treated with NIRT and how some must have been left feeling.

        I’m equally so chuffed that you are telling us how it is in this post (and many others provided by yourself, MD and the rest of the team) because so few of your fellow clinicians do so! There’s no doubt some PwMS will have been facilitated in having meaningful discussions with their HCP thanks to this post.

        It also made me feel that I shouldn’t sit back in some cosy sense of security that I’ve had Alemtuzumab, and had me wondering what I can possibly do to help myself. I needed to be more informed about brain atrophy and critically whether it’s feasible to offset, for want of a better word, brain volume loss. Consequently, I’ve been trawling the internet. That’s really emphasised: benefit of not smoking, limited drinking, the Mediterranean diet, exercise, more exercise and a dollop of meditation. One webpage states that there’s ‘compelling evidence’ that resistance and endurance exercise is good for the brain – and it’s about a study of PwMS.

  • I thought you believed cladribine was a game changer, but now it turns out that it’s blah? You’re enthusiasm and reading of others hpnourney on it and the studies made me chose this treatment but now I’m questioning whether I’ve made a mistake.

    • It is still a game changer, but not a panacea, and that is the point I am trying to make by thinking beyond NEDA. A lot of pwMS are still being walked through 5-6 tiers of treatment over 10-15 years before they get to the upper tiers.

      • Thank you for replying. Must admit I’m disheartened though after reading this. I went in to this with such positivity, delayed treatment by a few months as I was waiting for cladribine but now I’m back to the worry of “will I be in a wheelchair in 3 years” even though I’m a 0 on the scale of disability now. Huge worry now and back to having to search for another treatment after this by the sounds of it. Whereas I was telling everyone, this is it, great results etc. I know it doesn’t stop but slows disability, but this sounds like it doesn’t slow it much at all. Thanks again for taking the time to reply.

        • It is important not to confuse your personal outcome with group averages. The important thing is to be monitored and to be retreated, escalated and changed if you are shown to be a non-responder. People on high-efficacy DMTs do very well, but potentially do even better on very high-efficacy DMTs. The problem we have is selecting who needs the latter first-line.

  • Noting these observations about the disappointing results for anti B Cell drugs in slowing brain atrophy, I am wondering if the apparently promising research of Pender et al in Australia targeting EBV and T Cells might have the potential to be used in conjunction with anti B Cell therapy

    • I don’t think we should say that the anti-B cell therapies have no impact on brain volume loss; they do but it is less than you expect compared to the NIRTs for similar NEDA rates. The question is why? Is this telling us something about the cause and pathogenesis of MS?

      • Until neurologists can give a better prognosis then I would imagine many people with MS would be very hesitant to take on board the very serious and potentially deadly side effects of the most potent treatments. And more problems seem to be emerging with Alemtuzumab as time goes on. Can we be confident at this stage that it will not ultimately have the same disappointing results as Rituximab after 10 plus years with people still progressing to SPMS? As you have previously commented on this blog:“…… my initial enthusiasm for ocrelizumab has been dampened by Steve Hauser’s comments that a large number of their patients with relapsing MS who have been treated for 10+ years on rituximab have now developed SPMS. If this is correct then anti-CD20 B-cell depletion will not be a panacea. ”
        Would you consider Natalizumab to be a considerably safer option than Alemtuzumab, despite the risk of PML, as long as the test for the JCV is negative?

        • If someone is JCV-ve natalizumab is definitely a safer high-efficacy drug compared to the NIRTs (alemtuzumab and HSCT). I have several patients from the AFFIRM study who have now been on natalizumab 15+ years and are still fully functional and stable (NEDA). Whether they are really fine I am not 100% sure as I have not been monitoring their cognition, brain volume, CSF neurofilament levels, etc. We are now beginning to implement annual monitoring with the SDMT. So yes for MSers who are JCV-ve and NEDA staying on natalizumab is a very reasonable thing to do.

          • Many thanks for your reply. What really concerns me about Natalizumab is the issue of potentially catastrophic rebound if the need arises to stop and move onto another DMT.

  • Thank you Prof G. Can we be confident that ALL neurologists throughout the UK know how to prevent rebound following treatment with Natalizumab? Which DMTs do you tend to use at Barts after stopping?

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