Beyond the B-cell: cognitive dissonance


I continue to be amazed when I hear senior MS neurologists make the claim they have never prescribed alemtuzumab or referred any of their patients for HSCT and don’t intend to do so either. These same neurologists seem to be happy with natalizumab and ocrelizumab as their #1 high-efficacy go to DMTs. When I challenge them with the exceptional longterm outcomes for pwMS treated early with alemtuzumab or HSCT I get a glazed look, which I now learnt is cognitive dissonance

“Cognitive dissonance refers to a situation involving conflicting attitudes, beliefs or behaviours. This produces a feeling of mental discomfort leading to an alteration in one of the attitudes, beliefs or behaviours to reduce the discomfort and restore balance. For example, when people smoke (behaviour) and they know that smoking causes cancer (cognition), they are in a state of cognitive dissonance.” Source: Simply Psychology

It is quite clear that both ocrelizumab and natalizumab are very effective DMTs at switching-off focal inflammatory disease activity in MS; a large number of pwMS on these therapies are NEDA-2 (relapse-free and no new T2 lesions on MRI). This is interpreted by these neurologists and the wider MS community that MS is all sorted. Go away, get on with your life and be happy.

What these neurologists don’t tell their patients on ocrelizumab and natalizumab that despite no relapses or new MRI lesions the accelerated brain volume loss due to MS is continuing unabated. These neurologists and their patients are being lulled into a sense of false security because they believe MS is focal inflammatory disease, when in fact the real MS is the smouldering disease, which drives end-organ damage. 

I have addressed these topics many times on this blog. If you are interested in reading some of my back catalogue of posts on this particular topic you can start with the posts below or you could watch a recent lecture I have given on the topic.  

It is clear that not all DMTs are made equal when it comes to preventing end-organ damage. 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 probably next with an annual brain volume loss in the region of 0.25-0.30% per annum. Ocrelizumab (anti-CD20) comes next with a rate of brain volume loss of ~0.374% per annum (see latest data below). 

Why do natalizumab and ocrelizumab, despite being very effective anti-inflammatory DMTs have only a moderate impact on end-organ damage? This and other observations have convinced me that MS is not focal inflammation, which represents the immune system’s response to what is causing MS. I suspect there is something going in the CNS of pwMS that is the real MS; I refer to this hypothesis as the ‘Field Hypothesis’.

What these observations are telling us that peripheral B-cells are an important part of the immune response to the cause of MS, but B-cells are not necessarily involved in driving the true MS pathology, which is causing the progressive brain volume loss. 

What does this mean for the well-informed person with MS? Firstly, you and your neurologist may not want to dismiss alemtuzumab and HSCT as a first-line, or at least early, treatment option. These non-selective highly effective IRTs differ from anti-CD20 therapies in that they target both B and T cells. I suspect we need to target both these cells types early in the course of the disease to really get on top of the real MS. 

I am aware of the appeal of anti-CD20 therapies and natalizumab in that they are safer and easier to use because of less monitoring, however, this may come at a cost in the long-term. Please remember that once you have lost brain you can’t get it back. With alemtuzumab and HSCT, the risk is frontloaded, and balanced against the potential long-term gains in efficacy, which are unprecedented. Choosing a DMT on a rung or two lower down on the therapeutic ladder gives you better short-term safety and makes the life of your MS neurologist less stressful, because of less monitoring and fewer risks, but at a potential long-term cost to your brain and spinal cord.  

This is why making an informed decision about which DMT you choose is a very complicated process and subject to subtle and often hidden effects of cognitive biases; cognitive dissonance is just one of these 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 eventually end-up losing.

In reality, we need to move treatment target in MS way beyond NEDA-2 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 few years. 

As yet we don’t know what the impact of alemtuzumab and HSCT are on the pathology of smouldering MS, but these agents must be doing something to these pathologies based on clinical and MRI outcomes (see below). Despite this data gap, I think we have enough empirical evidence that alemtuzumab and HSCT are doing some fundamental to the pathology of MS.  

Coming back to cognitive dissonance. It could be argued that if an MS neurologist or MS centre does not offer alemtuzumab or HSCT to at least some of their patients then they are not providing their patients with sufficient choice. In addition, they will almost certainly not accept the concept of smouldering MS being the real MS.


Hauser et al. Five-years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension. Neurology 2020; First published July 20, 2020, DOI:

Objective: To assess over 3 years of follow-up, the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA studies in relapsing multiple sclerosis.

Methods: After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN) β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression/improvement (CDP/CDI), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed.

Results: Of patients entering the OLE phase, 88.6% completed Year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier, vs patients initially receiving IFN β-1a (16.1% vs 21.3% at Year 5; p=0.014). Patients continuing OCR maintained, and those switching from IFN β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from Year 3 to 5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN β-1a (–1.87% vs –2.15% at Year 5; p<0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.

Conclusion: Compared with patients switching from IFN β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.

Classification of evidence: This study provides Class III evidence that earlier and continuous treatment with ocrelizumab provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.


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.


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.


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.


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.


          • we have been here before and this is where profG and I do not see eye to eye. The 0.5% from the CLARITY trial was 9 years after diagnosis contrast this with 0.2% in the ORACLE where cladribine was given before MS diagnosis at optic neuritis. the MS CARE I was 2 years from diagnosis MS-CARE 2 4 years from diagnosis. What does it show …lack of adequate effect on smouldering MS

          • MD: why is alemtuzumab’s brain atrophy figures ahead of the rest when, on average, only 40% suffer from thyroid autoimmunity?
            I am referring to the article you posted a couple of weeks stating that alemtuzumab has the highest efficacy in patients who actually end up taking daily thyroid pills.

          • Well that paper was very important in my view – we ought to keep coming back to it in the absence of more information.
            I am just not able to draw a full picture here just yet – lots of contradictions.
            The ultimate question to be answered in a gambler’s dilemma setting: what is optimal for a JCV- patient responding well to natalizumab yet seeing acute BVL on their MRI: to shift or not to shift?

          • Cant be pseudo after 10ys, right?
            Pseudo is just seen in the first 1-2 ys to my understanding….or what am I missing?
            Why are so many mabers xonverting to SPMS otherwise?

          • What are you missing… think we know what your scans were and when they were taken…we dont’

  • Nice article Prof G. I completely buy your hypothesis even though I’m not a trained Neurologost or immune specialist. But am a trained biochemical engineer and computer (AI) expert. So understand how biological processes work and able digest large amount information and apply for practical solutions. The point I want to make is a large part of your team still think MS is a B cell mediated disease. Who would gladly prescribe b cell therapies over alemtuzumab and HSCT. So Getting to the point if you can’t persuade your own colleagues what chance do you persuading others ?

    • B-cell therapies are very effective at what they do; stopping relapses and MRI activity. They are not so good at smouldering MS. I will have much more to say on this when the publication of ofatumumab vs. teriflunomide is published.

    • I would like to know how prof g feels about neurologists who choose to offer no treatment to deteriorating MS patients like my partner? We have now seen 3 who have offered nothing except being sent home with baclofen. Pretty poor service in my opinion, but no-one cares do they so he is left suffer (in constant terrible pain) whilst life gets harder and harder.

  • Prof G, I am due to start Ocrevus next week as a first line DMT. I was initially happy to be taking the ‘hit it hard and early’ route but having subsequently read a lot of posts on smouldering MS as well as the shortcomings of maintenance therapies, I am less enthusiastic. The thing is, we patients can only work within the confines of the system….I was offered Ocrevus or tecfidera and chose Ocrevus as the most effective. Hopefully it will keep relapse activity under control but that would only make my case to move to lemtrada or hsct harder (impossible based on recent experience) to make. So I will be left with the nagging doubt that I could be doing more / better. There seems to be a huge disconnect between what the science is telling us and what neurologists are actually carrying out in practice. How can this be fixed? I am gaining knowledge as I go so consider myself to be fairly well informed and I am also a complete nag, which perhaps has got me further than I would have otherwise. Without this I would of probably ended up on a low efficacy injectable but this will be the reality for some / a lot. This is not a criticism by the way, this blog is excellent. I just feel there is a gap between theory and practice, which will maybe only be bridged by funding

    • Completely agree with Anonymous above. Prof G – if your peers won’t listen to the science, then are we not just basically buggered?

      • Not really. PwMS on lower-tier DMTs still do relatively well, but just not as well as they could have done on the top-tiered DMTs. It is a numbers game. Some pwMS end-up doing well without treatment.

  • I have been on ocrelizumab since April 2019. Was initially also offered lemtrada but by the time I came to have the treatment lemtrada had been withdrawn as was under review. I had had already chosen ocrelizumab but if I’d chosen lemtrada I wouldn’t have been eligible. How does the pwMS make this choice now? What are the pros and cons for someone newly diagnosed? How does Prof G advise his patients as I know he still uses ocrelizumab?

    • It is called a catch-22. If the FDA had not licensed alemtuzumab 3rd-line, which drove the use of the drug in a very different population (older, more advanced disease, comorbidities, etc.) we may still have the drug 1st-line in Europe. The adverse events that resulted in alemtuzumab being restricted in Europe are because the drug was used in a high-risk population that was not studied in the CARE-MS1 and CARE-MS2 trials.

      One of the great tragedies of MS is the hand-cuffing of alemtuzumab as a treatment for MS.

      • Thanks Prof G,
        I was offered lemtrada as first line after having Rebif when CIS. I was nervous to have it due to all the side effects. My ms is mild with only sensory symptoms plus I’m older than your typical pwMS – 51 now. Also, my neurologist was keen on ocrelizumab so here I am. However, even if I had initially chosen lemtrada I wouldn’t have met the new criteria.
        Can I ask why your ocrelizumab patients don’t have lemtrada?

        • Ocrelizumab is first-line and alemtuzumab is limited to pwMS who have highly active MS. So most patients are not eligible for alemtuzumab under the NHS. In the past alemtuzumab was a 1st-line agent.

          • The decision was made for me tbh although I had already chosen ocrelizumab due to lower risks. Having said that, although I was initially offered lemtrada, I wouldn’t have been able to have it with the new criteria by the time I actually got the ocrelizumab.

          • Is that not a low bar?

            What about the convo that Ocrelizumab could be used as an induction therapy at some point? Is that possibly a thing?

      • It is a greater tragedy the company did not engage in mitigation strategies for SAI and/or trials in people with more advanced disease.

      • Prof G – you’ve written before about “de-risking” alemtuzumab, but what would that entail? And is Sanofi Genzyme working on that?

        • I think Sanofi-Genzyme have moved onto new pastures with the potential to be greener. Who knows?

          Very sad. We tried to get the rituximab post-alemtuzumab study funded to prevent secondary autoimmunity in 2014. We would have had results in 2018. Imagine a world in which we could use alemtuzumab safely and prevent secondary autoimmunity?

          • Thanks for your reply. I’m not a violent person so I will have to make do with punching a cushion! It’s tragic. Maybe I’m naive but I don’t understand why a drug company wouldn’t be interested in cooperating in studies to make their Products safer. ¯\_(ツ)_/¯

          • As a person who’s wife selected alemtuzumab first line, I wish this study had be conducted. She has now developed thyroid problems which is increasingly looking like Graves. I spoke with both her neurologist and endocrinologist about looking at her B cell count and the possibility of low dose rituximab (which I would pay for) but neither were willing to do either as they believe their is no evidence supporting the hypothesis. That is, the repopulation of B cells above baseline is causing the secondary autoimmune problems. I have subsequently emailed both a plethora of papers supporting the hypothesis. Let’s see what comes from it.

            No regrets with selecting Alemtuzumab first line. Reducing end organ damage was always top of our list.

          • I am not sure it will be able to stop the problem once it has arisen, at least from a short course. No evidence that disproves the hypothesis too. I is a very gooddrug but it could be made safer

          • Again I beg to ask the question. What is and how do you measure MS is in the early stages? Prey tell. Is it number and size of lesson? Or the Frequency of relapses? Or the percentage of Brain Atrophy? Or the number of functions? Whats your yard stick to say this patient is early or late?

  • Ludwig Kappos’ landmark article in JAMA Neurology (we in the MS world always knew about brain atrophy, volume loss, etc) showed us all that when relapse-free worsening of EDSS is carefully packaged away from a relapse-driven state by an interval of 90 days I suppose (it was not clear for me what this specific interval was, once the EDSS change to a higher value was documented, but it is safe to say that it was perhaps at least 90 days from a relapse), one can begin to see worsening of disease as pictured through an EDSS lens. His paper obviously does not correlate change in EDSS (which was actually worse w OCR as compared to an interferon beta-1a SC) to brain atrophy or any such pathological substrate but to your point regarding prevention of smoldering disease in MS and how best to address it with ALTZ or HCST, some of the reluctance, understandably, are side-effects, particularly w the drug.

    In the context of atrophy and MS, Dr Azevedo’s work published in NNN 2019, 6(6), comes to mind. Here are her findings:

    The top-ranked regions were all gray matter structures. For SIENA, normal aging increased from 0.01%/y at age 30 years to −0.31%/y at age 60 years (−0.11% ± 0.032%/decade, p < 0.01), whereas MS-specific atrophy decreased from −0.38%/y at age 30 years to −0.12%/y at age 60 years (0.09% ± 0.035%/decade, p = 0.01). Similarly, in the thalamus, normal aging increased from −0.15%/y at age 30 years to −0.62%/y at age 60 years (−0.16% ± 0.079%/decade, p < 0.05), and MS-specific atrophy decreased from −0.59%/y at age 30 years to −0.05%/y at age 60 years (0.18% ± 0.08%/decade, p < 0.05). In the putamen and caudate, normal aging and MS-specific atrophy did not vary by age.

    Given the above, and with SIENA and thalami showing us that MS-related atrophy DECREASES with age, how does it square with data derived from ALTZ ? Of course there is MS-related atrophy is focal as in focal thinning of cortex, and pathology related to B-cell subpial follicles, etc, but while we are on the subject of cortical or global atrophy, why in the MS world don't we even MEASURE these changes or seek to measure cortical changes (not to speak of deep gray matter nuclei changes, iron deposition, the works) using 7T (which is presumably the best modality to capture data on subpial B cell lymphoid follicles) or even use DIR routinely to seek cortical lesions at 3T ? We are still worried about WM lesions which is fine but what of the cortex ?

    So I guess there are lots of Qs. Taking stock, and then taking aim. We do not do the first of the two, and do not track changes routinely. We publish and then it is out there, we have a 7T in our backyard, we can publish. But we do not implement the changes to inform the patient, there are too many issues with standardization, definitions, guidelines, and even questions about what is normal vs. abnormal. And of course the patient does not know we do not have 7T at our disposal. They will, over time. The web makes sure of that.

    Therefore we are not answering the question of treatment (yet) since we are not even sure about the atrophy measurements. In the USA, we do not use FDA approved (icobrain and NeuroQuant) to document change. What the mind does not know, the eyes do not see.

  • For newly diagnosed patients this must be soul destroying to read because you can’t get HSCT or Lemtrada as a first line treatment. I was super fortunate to have Lemtrada as a first line 5 months before the review started from a forward thinking neurologist despite only having 3 lesions. I can’t image how I’d feel knowing I wasn’t being given the best option for my long term health.

  • Thank your for the data and thoughts.

    Ok HSCT cames with a better BVL on the long course than ocrelizumab (0.15% vs 0.35%) but with a big cost at front with 3.3% BVL so like 10 years of BVL on ocrelizumab (actualy more than ten years because the iteration of 10 years of 0.35% BVL yearly is smaller than 10×0.35%), so about purely BVL, it seems to me that HSCT is not that interesting.

    Or am I resoning baldly ? Does Alem show the same BVL cost at front ?

    • No the massive brain volume loss upfront with the myeloablative HSCT protocols is due to pseudoatrophy and chemobrain. Chemobrain is due to the neurotoxic effects of chemotherapy on the brains of pwMS.

      • Where do you stand on myeloablative vs non-myeloablative conditioning these days (I read the statement on the mini site as pro-myeloablative but that seems to be a couple years old by now)?

        All I can find is hints that EBMT data shows little difference in efficacy but no solid study…

  • Where are the numbers for Natalizumab coming from? Do you have research for brain volume loss on Natalizumab, like for HSCT/Ocrelizumab/Alemtuzumab?

    • Vidal-Jordana A, Sastre-Garriga J, Pérez-Miralles F, et al. Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes. Mult Scler. 2013;19(9):1175-1181. doi:10.1177/1352458512473190

      Eisele P, Szabo K, Ebert A, Platten M, Gass A. Brain Atrophy in Natalizumab-treated Patients with Multiple Sclerosis: A 5-year Retrospective Study. J Neuroimaging. 2019;29(2):190-192. doi:10.1111/jon.12586

      Masuda H, Mori M, Hirano S, et al. Comparison of brain atrophy in patients with multiple sclerosis treated with first- versus second-generation disease modifying therapy without clinical relapse [published online ahead of print, 2020 May 19]. Eur J Neurol. 2020;10.1111/ene.14335. doi:10.1111/ene.14335

      Arpín EC, Sobrino TG, Vivero CD, et al. Changes in brain atrophy indices in patients with relapsing-remitting multiple sclerosis treated with natalizumab. Neurodegener Dis Manag. 2016;6(1):5-12. doi:10.2217/nmt.15.53

      Sastre-Garriga J, Tur C, Pareto D, et al. Brain atrophy in natalizumab-treated patients: A 3-year follow-up. Mult Scler. 2015;21(6):749-756. doi:10.1177/1352458514556300

      Portaccio E, Stromillo ML, Goretti B, et al. Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing-remitting multiple sclerosis–a prospective, non-randomized pilot study. Eur J Neurol. 2013;20(6):986-990. doi:10.1111/j.1468-1331.2012.03882.x

      Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68(17):1390-1401. doi:10.1212/01.wnl.0000260064.77700.fd

    • Important to rebaseline brain volume after 6 or 12 months with an anti-inflammatory to get rid of the pseudoatrophy due to reducing inflammatory swelling of the brain that occurs in year 1. This is particularly prominent with natalizumab.

  • Great post! Very interesting! Among the many questions that came to my mind, one is on top: What is alemtuzumab killing beside B cells and T cells? It should not kill plasma cells and it should not get into the brain so it vould be targeting something in the periphery that may block the disease… or it is getting in the brain, even in small amounts, and effectively target something that is not targeted by ocrelizumab that is given in higher doses and for longer time (so the memory b cells full depletion is not enough to stop the disease). I am starting to be a bit lost! 🙁

    • Please note that alemtuzumab is only very effective when used early in MS. When given in well established MS its impact is less obvious. That is telling us something very important.

      • Prof G,
        what foes well established MS means?
        As we can see Care-MS II. was almost as robust as C-MS I. In spite of the more advanced MS (higher EDSS and longer disease duration).

      • Maybe it’s telling also that something in my post may not be fully correct…

        What does it mean early? Is it years from CIS, EDSS, number of lesions… don’t know….?

  • Would love to hear some guidance on having this discussion with one’s neuro. I have a feeling they are biased towards the non-IRT approaches much for the reason you outline…

  • ”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 probably next with an annual brain volume loss in the region of 0.25-0.30% per annum. Ocrelizumab (anti-CD20) comes next with a rate of brain volume loss of ~0.374% per annum (see latest data below).” Why is this presented as a fact when it is just a hypothesis derived by comparing the results of different clinical trials with different selection and other criteria. In lack of disease prognostic factors a randomized trial between all highly effective DMTs should be done before using lemtrada or HSCT as first line for MS given the side effects.

    • You didn’t miss anything; this is (almost) a postmortem of a compound that is highly effective and fraud with adverse problems, which weren’t properly addressed. You’re right, there are now significant limitations of getting it, whereas previously it had the lowest threshold of them all (in Europe).

      • OK. Why are the rest of Barts team quite. I do agree with Prof G that Alemtuzumab is superior to b cell therapy and Alemtuzumab can be derisked to mske safe with dose of ocrelizumab 6 months later. But if none of the rest of the team don’t speak how are we as patients to have a balanced view. Md where are u?

        • There is really no new information in this post. It is recycled data and concepts. The issue is what is the real MS? Is it relapses and focal MRI activity or smouldering disease? An interesting and important debate. Anti-B-cell therapies are pretty good at targeting the former, but poor at targeting the latter.

          • Prof G and MD – I’ve just been looking back through some old posts. Were your letters to the EMA regarding Alemtuzumab ever replied to?

  • Dear Prof G – great post, thanks

    Swedish NFL RWE (Delcoigne Neurology 2020) provides another verification of the hypothesis – only almetuzumab puts it into normal range. CD20 data for that study is incomplete in the delta effect, but in the absolute effect, rituximab is not in the normal range either. Yet again, by a different method, alemtuzumab achieves population normality (individuals wont), then natalizumab second, then others.

    BVL for alemtuzumab over Years 2-5 is better again: Average y2-5 = -0.195%/y CAREMS1, Average y2-5 = -0.095%/y CAREMS2, (P1189, Arnold & P741, Pelletier, ECTRIMS 2017), well into the normal range
    BVL for ocrelizumab over years 2-5 stays abnormal at Average Y2-5 = -0.37275%/y (P588, ECTRIMS 2018, Arnold et al)

    Quote: “Choosing a DMT on a rung or two lower down on the therapeutic ladder gives you better short-term safety and makes the life of your MS neurologist less stressful, because of less monitoring and fewer risks, but at a potential long-term cost to your brain and spinal cord.” – That’s why most neurologists don’t make strong arguments for alemtuzumab / AHSCT, because they like a low-stress dayjob. Those who do, do neurology as a vocation, not as a dayjob. I accept that some neurologists have been burnt, the side effects are real.

    In Australia we once unofficially & unpublished asked the neurologists what drug they would have if they got MS (it’s no longer the patient’s brain and spinal cord, they are the PWMS). Answers: natalizumab or alemtuzumab if JC negative, alemtuzumab if JC+, a few older neurologists said ocre, almost nobody for the middle ground orals, a few wanted a copaxone trial just in case it worked.

    Cheers, Fred

    • The neurofilament data may be another way of saying it gets rid of lesion better than anti CD20, but the data will be skewed as anti CD20 is used so frequently there is Swedish data saying the atrophy rate was 0.2% (same as alemtuzumab). again alemtuzumab is 2 years post diadgnosis and opera trial was 6 years. Maybe they simple need to do a head to head and put this issue to bed…

      Choosing a DMT a rung down is I am told done by Lazy neurologists in a certain country as they dont want monitoring issues…

      Results: The mean (standard deviation) age was 46.3 ± 12.2 years, 72% of the patients were female, on average the patients were 10.6 ± 8.7 years sick, the median EDSS was 3.0. The majority of patients suffered from a relapsing course (74.2%), 16.1% had a secondary course and 5.5% had a primary progressive course. Immunotherapy was performed in 75.2%, most often with interferons, followed by fingolimod, glatiramer acetate, dimethyl fumarate, natalizumab and teriflunomide…..Guess which country this is. You know it isnt the UK if 75% are being treated.

  • I am receiving Ocrevus at the moment. I had Lemtrada earlier on post-diagnosis (2 courses – last one 2015) but my MS is active again. I avoided Lemtrada this time because of Coronavirus concerns. I had two questions if you’re able to provide your insight:

    1. Leaving aside eligibility etc would you recommend switching from Ocrevus to a third Lemtrada dose, once Corona conditions are a lesser factor? I tolerated it very well and have had no secondary autoimmunity issues.

    2. Other than Lemtrada and HSCT, is there any treatment currently available (again, ignoring eligibility, funding constraints) that is believed to be effective at ‘scrubbing the brain’/smouldering MS? You mention Teriflunomide quite a lot as a sort of dark horse. Do you believe this might be effective on smouldering MS? Could this be taken in combination with Ocrevus? You also refer to high dose Ocrevus as a possibility for penetrating the BBB – is this purely hypothetical or could a neuro prescribe a higher dose assuming a willing patient?

    The notion that we are treating just one ‘acute’ part of the condition whilst slowly declining regardless because of an untreated primary mechanism is quite unsettling, hence these questions!

    Thanks for all your contributions via this site.

    • Lemtrada and HSCT probably have no power to scrub the brain clean as they dont get into the brain to any large exent. However they may remove the conditions that create the smouldering MS.
      About 50% fail two alemtuzumab couses and 50% fail a third meaning 75% get good remission after two 2-3 cycles.

      Teriflunomide and ocrevus em….ocrevus is present for some time.

      High dose ocrevus this may be relevant if you have a high BMI.

  • Hi prof g ! Massive fan have been going back reading your old posts since i was diagnosed this year ! I am trying my best to get an effective induction therapy however my neuro wont give me the time of day and ive been offered nothing since my diagnosis ! How are we supposed to get effective treatments early if we are just ignored by neurologists !

By Prof G



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