Which side of the fence are you on?

Barts-MS rose-tinted-odometer: zero-★s (still seeing red)

Apologies some more definitions: 

Side of the fence: used to refer to either of the opposing positions or interests involved in a particular situation.

Status quo: the current situation; the way things are now. The MS community, i.e. patients and HCPs are content with the status quo and aren’t looking for a change. 

NEDA: no evident MS disease activity

The question you need to ask yourself is which side of the fence are you on? MS is a focal inflammatory disease of the central nervous system vs. MS is a smouldering disease process and focal inflammatory events are in response to what is causing the disease. If you favour the former you will be happy with being NEDA-2, i.e. having no relapses or new focal inflammatory lesions. If you are in the latter camp you will want to focus on end-organ damage and preserving your brain and spinal cord volume for old age. 

The wider MS community seems to prefer the current dogma and status quo; i.e. that MS is a focal inflammatory disease and that everything we see can be explained by relapses and focal MRI activity. I think this is wrong and have argued this from not only a scientific point of view but also from a philosophical one. 

Deciding which side of the fence you are on may make an enormous difference to your outcome. It is clear that not all DMTs are made equal when it comes to preserving brain volume and hence brain reserve. 

Did you know that pwMS lose brain volume at a 2-7x faster rate than age-matched controls from the general population? Accelerated brain volume loss predicts and is strongly associated with cognitive impairment and long term disability. The following picture shows you just how much brain someone with MS can lose over an 18 month period. 

If we moved our treatment target to go beyond NEDA to focus on protecting the end-organ so that pwMS may have a brain that is in good enough condition to withstand the ageing process in later life I suspect the treatment landscape would change dramatically. To achieve this we need to diagnose MS and treat it early and effectively and in many cases, we need to flip the pyramid and use high efficacy therapies at the beginning, in particular agent such as alemtuzumab and AHSCT, which have been shown to protect the end-organ better than other DMTs. 

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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.

How is your end-organ functioning?

Barts-MS rose-tinted-odometer: ★

My prediction or dream for 2021 is that smouldering MS will be accepted by the wider MS community as being the ‘real MS’ and that simply suppressing the immune response to what is causing MS, i.e. relapses and/or focal MRI activity, will be accepted as folly. What matters most to pwMS will be their end-organ, i.e. the size, reserve capacity and function of their brains and spinal cords. 

In the same way as patients with a chronic heart or kidney disease ask their cardiologists or nephrologists what is my cardiac ejection fraction or creatinine clearance, markers of end-organ function of the heart and kidneys, respectively, I suspect pwMS will be asking what is the current state of their brains and spinal cords and how has the measures changed from last year. To answer our patients’ questions we are going to have much better functional and structural outcome measures or just maybe patients will be telling us how they are doing via their own self-monitoring initiatives.

The two studies below one looking at the thickness of retinal layers in the eye and the other the size of the thalamus, or deep grey matter structures, in the brain, show that loss of neurons or atrophy predicts future disability.  The problem I have with anatomical studies is that by the time you measure and show loss of neurons or atrophy it is too late, i.e. the damage is done and is irreversible. There is data out there that shows loss of function precedes the loss of neurons and that some of the early loss of function may in fact be reversible. Therefore we are going to need to measure function as well as structure. 

It is clear that our current clinical outcome measures are too insensitive to change, which is why we are going to need more sensitive and frequent monitoring of function to get on top of smouldering MS. The question is ‘so what if you detect subclinical worsening of function in MS what are you going to do about it?’. In the future, we will be adding-on new therapies to existing anti-inflammatory DMTs that will allow us to go beyond NEIDA (no evident inflammatory disease activity) to tackle smouldering MS. I am acutely aware that we are not there yet when it comes to combination therapies, but that is clearly the direction of travel the MS community is heading. Let’s hope the regulators agree and support the emerging development framework for combination therapies and allow us to start as many trials as soon as possible.

So if you are an MSologist and are reading this post don’t be too surprised if your patients start demanding more detailed functional and structural monitoring of their brains and spinal cords. Wouldn’t you if you had MS?

Retinal thinning in MS

Maria Cellerino et al. Relationship Between Retinal Layers Thickness and Disability Worsening in Relapsing-Remitting and Progressive Multiple Sclerosis. J Neuroophthalmol. 2020 Dec 29. 

Background: Data regarding the predictive value of optical coherence tomography (OCT)-derived measures are lacking, especially in progressive multiple sclerosis (PMS). Accordingly, we aimed at investigating whether a single OCT assessment can predict a disability risk in both relapsing-remitting MS (RRMS) and PMS.

Methods: One hundred one patients with RRMS and 79 patients with PMS underwent Spectral-Domain OCT, including intraretinal layer segmentation. All patients had at least 1 Expanded Disability Status Scale (EDSS) measurement during the subsequent follow-up (FU). Differences in terms of OCT metrics and their association with FU disability were assessed by analysis of covariance and linear regression models, respectively.

Results: The median FU was 2 years (range 1-5.5 years). The baseline peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) were thinner in PMS compared with RRMS (P = 0.02 and P = 0.003, respectively). In the RRMS population, multivariable models showed that the GCIPL significantly correlated with FU disability (0.04 increase in the EDSS for each 1-μm decrease in the baseline GCIPL, 95% confidence interval: 0.006-0.08; P = 0.02). The baseline GCIPL was thinner in patients with RRMS with FU-EDSS >4 compared with those with FU-EDSS ≤4, and individuals in the highest baseline GCIPL tertile had a significantly lower FU-EDSS score than those in the middle and lowest tertile (P = 0.01 and P = 0.001, respectively). These findings were not confirmed in analyses restricted to patients with PMS.

Conclusions: Among OCT-derived metrics, GCIPL thickness had the strongest association with short-medium term disability in patients with RRMS. The predictive value of OCT metrics in the longer term will have to be further investigated, especially in PMS.

Thalamic atrophy in MS

Burggraaff et al. Manual and automated tissue segmentation confirm the impact of thalamus atrophy on cognition in multiple sclerosis: A multicenter study. Neuroimage Clin. 2020 Dec 25;29:102549.

Background and rationale: Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining.

Methods: Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor.

Results: In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values < 0.001). All methods significantly distinguished CI from CP MS patients, except manual outlines of the left thalamus (p = 0.23). Poorer global neuropsychological test performance was significantly associated with smaller thalamus volumes bilaterally using all methods. Vendor significantly affected the findings.

Conclusion: Automated and manual thalamus segmentation consistently demonstrated an association between thalamus atrophy and cognitive impairment in MS. However, a proportional bias in smaller thalami and choice of MRI acquisition system might impact the effect size of these findings.

CoI: multiple

Twitter: @gavinGiovannoni                                       Medium: @gavin_24211

Teriflunomide’s secrets

Barts-MS rose-tinted-odometer: ★★★★★

What should be our therapeutic target in MS?  Reducing relapses and MRI activity, NEDA (no evident disease activity) or saving the end-organ (brain volume loss)? 

I have been pushing the for the latter, i.e. the most important treatment target must be protecting the end-organ and saving or protecting as many neurons, axons and synapses as possible in people with MS (pwMS) so that can age normally and live as near normal life as possible. To achieve this we need to diagnose and treat MS as effectively as possible (Time is Brain) and to promote a brain-healthy lifestyle and to treat MS holistically (minimal gains hypothesis).

This principle of protecting the end-organ is not new and was probably first promulgated by the kidney doctors in relation to loss of kidney function in chronic kidney disease; every nephron (the kidney’s equivalent of a neuron) is sacred. Every neuron is sacred! The difference between kidney doctors and neurologists is that they can always put their patients on dialysis and offer them kidney transplants. We, neurologists, don’t have that luxury and what awaits our patients with progressive loss of end-organ (brain atrophy) is unemployment, worsening cognitive impairment and physical disabilities and the consequences (bladder, bowel, falls, walking aids, wheelchairs, dementia, etc). 

What is interesting is that not all DMTs are made equal when it comes to protecting the end-organ. At the top of the rankings are HSCT and alemtuzumab followed by natalizumab and then there are the also-rans. What is interesting is the impact on brain volume loss is not necessarily linked to the DMTs ability to switch of focal lesions (relapses and MRI activity). A good example of this is teriflunomide, which has only a modest effect on relapses (~35% reduction in relapse rate) compared to say anti-CD20 therapies, which after 6 months of treatment almost completely stop relapses and MRI activity, but these two classes of therapy have a similar impact on slowing down brain volume loss. 

Teriflunomide is clearly doing something at the level of the end-organ that anti-CD20 therapies are not. This study below in subjects with CIS shows that teriflunomide works very well, on the end-organ, even early on in the disease, but not all subjects are responders. This begs the question; what is it about teriflunomide’s mode of action that explains its remarkable effects on brain atrophy? I have hypothesised in the past about teriflunomide’s broad-spectrum anti-viral effects and have proposed doing the iTeri study, i.e. using an anti-CD20 or other depleting DMT as true induction therapy and then using teriflunomide (or another DHODH inhibitor) as the maintenance therapy. The hypothesis is to allow peripheral B-cell reconstitution or recovery to occur in the presence of anti-EBV agents, which will prevent EBV-infected autoreactive (MS causing) B-cells returning. The problem we are having with the iTeri study is trial design; i.e. how do you design a trial that will convince the regulators of its efficacy and get the drug licensed as a maintenance therapy? Would the regulators accept non-inferiority or safety design? Another reason for this study design is to derisk anti-CD20 therapies. The doubting Thomas in me is saying there is no way someone with MS can stay on an anti-CD20 therapy indefinitely. 

Maybe I am wrong, but let’s not stick our heads in the sand. Relapses and focal MRI activity are not MS. The real MS is smouldering MS and all the processes that cause accelerated brain volume loss. Let’s focus on smouldering MS and ask questions about what needs to be done to tackle these processes. What is ot about HSCT, alemtuzumab, natalizumab and possible teriflunomide that differentiates the DMTs into two classes. For example, could it be the T-cell? 

Zivadinov et al. Slowing of brain atrophy with teriflunomide and delayed conversion to clinically definite MS. Ther Adv Neurol Disord. 2020 Nov 11;13:1756286420970754. 

Background: We explored the effect of teriflunomide on cortical gray matter (CGM) and whole brain (WB) atrophy in patients with clinically isolated syndrome (CIS) from the phase III TOPIC study and assessed the relationship between atrophy and risk of conversion to clinically definite MS (CDMS).

Methods: Patients (per McDonald 2005 criteria) were randomized 1:1:1 to placebo, teriflunomide 7 mg, or teriflunomide 14 mg for ⩽108 weeks (core study). In the extension, teriflunomide-treated patients maintained their original dose; placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Brain volume was assessed during years 1-2.

Results: Teriflunomide 14 mg significantly slowed annualized CGM and WB atrophy versus placebo during years 1-2 [percent reduction: month 12, 61.4% (CGM; p = 0.0359) and 28.6% (WB; p = 0.0286); month 24, 40.2% (CGM; p = 0.0416) and 43.0% (WB; p < 0.0001)]. For every 1% decrease in CGM or WB volume during years 1-2, risk of CDMS conversion increased by 14.5% (p = 0.0004) and 47.3% (p < 0.0001) during years 1-2, respectively, and 6.6% (p = 0.0570) and 35.9% (p = 0.0250) during years 1-5. In patients with the least (bottom quartile) versus most (top quartile) atrophy during years 1-2, risk of CDMS conversion was reduced by 58% (CGM; p = 0.0024) and 58% (WB; p = 0.0028) during years 1-2, and 42% (CGM; p = 0.0138) and 29% (WB; p = 0.1912) during years 1-5.

Conclusion: These findings support the clinical relevance of CGM and WB atrophy and early intervention with teriflunomide in CIS.

If you enjoy reading this blog you may want to support Prof G’s challenge

After his recent accident in which he sustained a broken pelvis and cervical spine, he has set himself a rehab challenge to walk 5 km unsupported by the end of the year (‘Prof G’s bed to 5km Challenge’). He is raising money for Queen Mary University of London to support Dr Ruth Dobson and Dr Angray Kang’s COVID-19 MS Antibody Study. So please donate if you can, every little helps and will get this study completed on time.

CoI: multiple

Twitter: @gavinGiovannoni 

Medium: @gavin_24211

Beyond NEDA: protecting the end-organ or your brain

Barts-MS rose-tinted-odometer: zero-★’s 

It became clear to me at least 6 years ago that we need to go beyond NEDA (no evident disease activity) when treating MS and we have to focus on protecting the end-organ, i.e. normalising the brain volume loss that occurs in people with MS (pwMS). To do this you really need to diagnose and treat MS as effectively as possible early on. From a research perspective, this means a focus on smouldering MS and the mechanisms responsible for the smouldering disease or the ‘real MS’.

This study below is another study showing a link between brain atrophy and cognitive impairment and supports the therapeutic strategy above. The criticism that is alway levelled at the flipping-the-pyramid argument is that too many pwMS will end up on high-efficacy DMTs and then what? My response to this is that if the majority of pwMS end-up on high-efficacy DMTs eventually is a testament to fact that the majority of pwMS need high-efficacy DMTs and hence it is best to get them there as soon as possible (#TreatMSASAP). 

This #TreatMSASAP principle underpins our #AttackMS trial design of using natalizumab ASAP after presentation and is aping the management of stroke. 

Another argument about flipping the pyramid is safety, i.e. we are putting pwMS at risk of severe adverse events. Yes, we are, but we can derisk a lot of the anticipated adverse events, i.e. the known-knowns and the unknown-knowns (anticipated AEs based on the mode-of-action of DMTs). In any event it is not for the neurologist or HCP to make the call on risk; surely it is up to the person with the disease to make the call? 

The following is a recording of my presentation from ACTRIMS-ECTRIMS 2020 that discusses these issues. Please note the presentation is targeting HCPs, but most pwMS should understand it. 

Golan et al. The association between MRI brain volumes and computerized cognitive scores of people with multiple sclerosis. Brain Cogn 2020 Sep 11;145:105614. doi: 10.1016/j.bandc.2020.105614. Online ahead of print.

Background: Computerized cognitive assessment facilitates the incorporation of multi-domain cognitive monitoring into routine clinical care. The predictive validity of computerized cognitive assessment among people with multiple sclerosis (PwMS) has scarcely been investigated.

Objective: To explore the associations between brain volumes and cognitive scores from a computerized cognitive assessment battery (CAB, NeuroTrax) among PwMS.

Methods: PwMS were evaluated with the CAB and underwent brain MRI within 40 days. Cognitive assessment yielded age- and education-adjusted scores in 9 cognitive domains: memory, executive function, attention, information processing speed, visual-spatial, verbal function, motor skills, problem solving, and working memory. The global cognitive score (GCS) is the average of all domain scores. MRI brain and lesion volumes were assessed with icobrain ms, a fully automated tissue and lesion segmentation and quantification software.

Results: 91 PwMS were included [Age: 52.1 ± 11.7 years, 64 (70%) female, EDSS: 3.4 ± 2.0, 79 (87%) with a relapsing-remitting course]. Significant correlations were found between the GCS and whole brain, white matter, grey matter, thalamic, lateral ventricles, hippocampal and lesion volumes (Correlation coefficients: 0.46, 0.40, 0.25, 0.42, -0.36, 0.21, -0.3, respectively). Regression analysis revealed that lateral ventricles and thalamic volumes were the most consistent predictors of all cognitive domain scores.

Conclusion: Computerized cognitive scores were significantly associated with quantified MRI. These findings support the predictive validity of multi-domain computerized cognitive assessment for people with multiple sclerosis.

CoI: multiple Twitter: @gavinGiovannoni  Medium: @gavin_24211

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.

OCRELIZUMAB BRAIN VOLUME DATA

Hauser et al. Five-years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension. Neurology 2020; First published July 20, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010376

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.

HSCT BRAIN VOLUME DATA 

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.

ALEMTUZUMAB BRAIN VOLUME LOSS

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.

ALEMTUZUMAB MRI END-ORGAN DATA

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

A sequence of losses

Prof G has the MS community go it wrong?

In this week’s NEJM there is an insightful perspective by Louise Aronson on ageing and driving.

Aronson. Don’t Ruin My Life — Aging and Driving in the 21st Century. N Engl J Med 2019; 380:705-707.

Louise quotes the American poet Donald Hall, who explains in Essays After Eighty how life is irrevocably and excruciatingly changed when a person must let go of their car: “For years I drove slowly and cautiously, but when I was eighty I had two accidents. I stopped driving before I killed somebody, and now when I shop or see a doctor, someone has to drive me. …Old age is a ceremony of losses.”

Although this refers to old age the same can be said for someone with MS. MS is a sequence of losses. Does it have to be this like this? I hope not, but to get to this position we need to go beyond NEDA.  

I am running one of our Barts-MS teaching programmes this week in which a case was presented by one of the delegates. The lady, who is in her early thirties, has a diagnosis of relapsing MS and is NEDA, off therapy for 5 years, i.e. no relapses and no new T2 lesions. However, when you look at her sequential MRIs next to each other it is clear that she has progressive brain volume loss. She has NEDA-3, but clearly, something else is happening to her brain. I suggested to the neurologist looking after this patient to interrogate her in detail, i.e. to measure her brain volume, send her for cognitive testing, arrange for a more objective interrogation of her neurological functioning and to do a lumbar puncture to assess if she has inflammation and ongoing damage as measured by CSF neurofilament levels. In other words, don’t rely on what we have now to assess her MS disease activity.

The problem we have is that we have created a beast called NEDA and the wider MS community now think evident disease activity or EDA (relapses and focal MRI activity) is MS. EDA is obviously not MS. It is clear that EDA in untreated patients is a very poor predictor of outcome. IF EDA was MS it would predict outcome regardless of being treated or not. In other words, EDA fails one of Prentice’s criteria for being a surrogate marker of MS.

Despite writing frequently on the topic that MS is not due to relapses and/or focal MRI activity the dogma seems to stick. I have arguably helped create NEDA as a treatment target and have been responsible for some of its stickiness as a treatment target. Can I admit I am wrong? NEDA is a useful construct, but it is now becoming a barrier to treating MS properly.

If I was a behavioural psychologist I would be referring to NEDA as the new cognitive bias. We need to shift our worldview of MS away from an MRI worldview. What we should be doing is creating a biological worldview of MS and asking what is happening in the ‘field‘ or the brains of people with MS. We have to explain why end-organ damage is ongoing despite switching off focal inflammatory activity. What is driving SELs (slowly expanding lesions), the subpial cortical lesion, grey matter atrophy and the accelerated brain volume loss? If we don’t then MS will remain a sequence of losses.

Playing second fiddle to the Swedes

Why can’t we use anti-CD20 therapies as immune constitution therapies?

For some years we have been promoting our Barts-MS Essential DMT list to treat people with MS (pwMS) in resource-poor environments. One of the big guns on our list has been rituximab (anti-CD20).  One of the problems is that rituximab at a dose of 1g every 6 months is still too expensive to accessible for the vast majority of MSers living in these environments. The good news is that several developments have brought the price of rituximab down.

  1. The Swedes, who are treating more than half their MS population, have data showing that 500mg every 6 months is as good as 1g every 6 months in terms of NEDA, i.e. preventing new relapses and new MR lesions from forming.
  2. Rituximab has come off patent and several cheap biosimilars are now entering the market.
  3. The Swedes are also testing adaptive dosing, i.e. after 2 years of 6 monthly infusions, they are extending the interval between doses to 12 months or more and/or are even beginning to redose rituximab based on peripheral memory B-cell reconstitution.  At a recent meeting, I was at one Swedish neurologist is beginning to use rituximab as an IRT (immune reconstitution therapy), i.e. only redosing with rituximab if and when disease activity re-emerges.

I classify anti-CD20 therapies as both a maintenance therapy and an IRT. At the last AAN in Los Angeles, I attended a meeting of like-minded clinical scientists to set-up a trial to test anti-CD20 as a maintenance therapy vs. an IRT. The retreatment arms of the trial were to test redosing based on the reemergence of disease activity or the repopulation of memory B cells. Using anti-CD20 therapies as an IRT has appeal as it will almost certainly be safer in terms of infections, the emergence of hypogammaglobulinaemia and ability to respond to vaccines.

I am therefore very interested in seeing the results of the Swedish experiment of testing rituximab as a maintenance therapy vs. rituximab as an IRT. Just maybe we can get the price of treating MS with rituximab down to affordable levels for low-income countries.

The following is a back of envelope calculations based on the current BNF prices:

Mabthera (Roche) 500mg = £873.15 per 500mg vial
Rixathon (Sandoz) = £785.84 per 500mg vial
Truxima (Napp) = £785.84 per 500mg vial

  1. Standard dose (1g) Mabthera maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £873.15 x 10= £8731.50 for the first 2 years and then £3492.60 annually.

  2. Standard dose (1g) biosimilar maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £785.84 x 5 = £7858.40 for the first 2 years and then £3143.36 annually.

  3. Reduced dose (500mg) Mabthera maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £873.15 x 10= £4365.75 for the first 2 years and then £1746.30 annually.

  4. Reduced dose (500mg) biosimilar maintenance regimen: 1g Day 0, 500mg Day 14 then 500mg 6 monthly indefinitely = £785.84 x 5 = £3929.20 for the first 2 years and then £1571.68 annually.

  5. Reduced dose (500mg) biosimilar maintenance regimen: 500mg Day 0, 500mg Day 14 then 500mg 6 monthly indefinitely = £785.84 x 5 = £3929.20 for the first 2 years and then £1571.68 annually.

  6. Adaptive dose (500mg) biosimilar maintenance regimen: 500mg Day 0, 500mg Day 14 then 500mg 6 monthly for 2year and then 500mg approximately every 12 months = £785.84 x 5 = £3929.20 for the first 2 years and then £785.84 annually (the latter may be lower if redosing is done using peripheral B cell reconstitution).

Please note these figures are the list price and don’t include discounts, VAT nor the infusion costs. In reality, these costs could come down with central, say NHS, purchasing power. Unfortunately, they are still too high to help pwMS in low-income countries. Just maybe getting MS and anti-CD20 therapies onto the WHO Essential Medicines List may bring down the costs by creating political pressure on the Pharma industry or innovations in making cheap biosimilars may also help.

The Caveat

There is one major caveat I have about putting up anti-CD20 as the solution for MS is that we may be getting it wrong. I personally don’t think relapses and focal MRI activity are the disease we call MS; these markers are an inflammatory response to what is causing the disease. Therefore I suspect we may be lulling ourselves into a false sense of security with anti-CD20 therapies and ignoring what is really driving the disease, i.e. what is causing the end-organ damage in MS.  

Do we know what is driving the slowly expanding lesion? What is causing the extensive cortical lesions in MS, which we can’t see on conventional MRI? What is driving the progressive brain volume and grey matter loss in MS? Don’t we need to go beyond NEDA as a treatment target? I know some would argue we have done this already, which is why so many MSers want HSCT as a first-line treatment option.

Prof G how much brain have I lost this year?

How soon will MSers have brain volume measurements as part of their annual assessments?

As a reader of this blog, you may be aware that ‘life is a sexually-transmitted age-dependent terminal neurodegenerative disease’. Homo sapiens, as a species, is pushing its biological capabilities to its limits. We have conquered most diseases that used to cull us before our mid-thirties and the end of our reproductive age. In the same way, as the technology sector has learnt to build in senescence into its products to ensure we upgrade our gadgets every 18-24 months, evolution has selected for biological senescence to make sure the current generation does not freeload on the next generation. When we have finite resources, why should we waste precious food on the older generation when we have to ensure the current generation reproduces to pass on its genes? A counter-argument to this ruthless biological perspective is that cultural evolution now takes precedence over biological evolution and it is societies and not individuals who are driving evolution. Culture and some heritable traits have clearly interacted with our environments, which explains why some isolated populations are enriched for people who are healthy agers. We are learning from studying these populations and unpacking the relevant biology to identify future treatment targets for healthy ageing. Do you want to be a healthy or super ager? If you have MS this is unlikely to happen.

These insights are telling us ageing is a biological process and therefore hackable, i.e. we will at some point learn how to reprogramme ourselves to reverse or at a minimum delay the effects of ageing. The reason I say this that we already do this in the form of reproduction; we produce sperm and eggs that go onto to recombine and form offspring that have their senescence programmes set to zero. Why can’t we do this at any stage of life?

Cellular senescence is accelerated by various stressors, which at the level of the whole organism results in premature ageing. The corollary of this is that certain lifestyle interventions appear to delay ageing mechanisms, or at least increases the resilience of the organism so that the consequences of ageing only become apparent much later on in life. Our increasing ability to manipulate these stressors and/or resilience mechanisms should empower individuals to maximise their health and wellness for future gain.

Is this relevant for MS? Yes, it must be. Firstly, many of the cellular stressors that result in ageing are upregulated in the brains of  MSers. We also know that one of the resilience mechanisms that protects us from age-related cognitive impairment is brain and cognitive reserve. As MSers get old you rely on these exact same mechanism to allow yourselves to age healthily. If you get to old age with a deficit how can you expect to age normally? As MS starts to shred your brain reserve from the earliest stages of the disease the treatment objective should be to address this from the outset? Therefore, how do we get the MS community to shift its treatment target beyond NEDA and to focus on the end-organ and the preservation of brain reserve?

One possible option would be to equip MS healthcare professionals (HCPs) and you the MSers with the tools to monitor end-organ damage more closely. Wouldn’t you want to know what is happening to your brain volume on an annual basis? Would you want to know if you are losing more brain than average?

Several companies are beginning to scale up their image analysis software and providing it online for MS centres and possibly individuals to measure their own brain volume and to get feedback based on a normogram; i.e. a normal distribution of brain volumes for age and to plot where on the standard curve you are. Your brain volume can then be measured and plotted annually to establish your trajectory.

The naysayers will say that this technology can’t be used on an individual basis as it has not been validated in clinical practice. The naysayers are in for a big surprise; I suspect the regulators are will approve these algorithms long before they are ready to incorporate them into routine clinical care. However, these very same naysayers often present group data at meetings with great confidence. Group data is what it is, an academic construct, that is far removed from clinical care and the individual with MS. My personal opinion about biomarkers is that you need to put them out there, with obvious disclaimers, and see how they are used. Technology itself works magic in many different ways.

I think having personal annual brain atrophy data will get both the neurologists, other HCPs and MSers to think differently about managing MS and it may be the nudge we need to treat MS more effectively early on and to change our treatment target. I also have little doubt that the methodology of measuring whole brain volume, grey and white matter volumes, lesion volume and the number and volume of lesions expanding will only get better and more accurate with time. So bring it on!

Do you agree with me? If not, let’s have a debate. End-organ damage and brain volume is very topical at the moment.

CoI: multiple

NEDADI or ‘Nee Daddy’ another treatment target beyond NEDA

Prof G do you think disability improvement is a reasonable treatment goal?

NEDADI = no evident disease activity and disability improvement

Two weeks ago one of my patients with PPMS, who we treated with off-label subcutaneous cladribine, came for her annual follow-up appointment. Despite being treated with cladribine over 2 years ago she has unfortunately progressed from EDSS 5.5 to 6.5. Her latest MRI brain did not show any new T2 lesions. She asked why we hadn’t scanned her spinal cord. She is desperate for us to find some disease activity so that she can be retreated or preferably offered ocrelizumab. She has a well-off family member who is prepared to cover the costs of ocrelizumab treatment privately. What should I do?

As you know I don’t support private prescribing in the NHS as it undermines the NHS’ founding principles; free at the point of access and equity. However, it is difficult to say no to private prescribing if a patient insists, particularly as there is now a mechanism to do this under the NHS. I am also first a doctor looking after the individual patient and this takes priority over my duty as an NHS employee and guardian of its socialist healthcare ideals.

I didn’t agree to a private prescription for ocrelizumab. Instead, I batted the problem into the long grass and agreed to bring her via our planned investigation unit for an MRI of the spine and lumbar puncture to measure CSF neurofilament levels. If there are new spinal cord lesions and/or a raised CSF neurofilament level then we could potentially look at an additional course of cladribine, off-label rituximab under the NHS, private ocrelizumab or possible recruitment into a clinical trial. I suspect that the MRI will show no new lesions and the CSF NFL levels will be normal. If this is the case then she has NEDA with worsening disability. I did refer her to my blog post on this issue (EXPLAINING WHY YOU GET WORSE DESPITE BEING NEDA) so she could get some understanding of what was happening to her.

During the consultation, she asked me ‘why a friend’s daughter with very bad MS, who had been treated with alemtuzumab, had made such a remarkable recovery?’ Apparently, this young woman had been rendered partially paraplegic from a spinal relapse and after alemtuzumab had recovered function and was now walking almost ‘normally’ again. My patient wanted to know why there was such a difference between herself, someone with PPMS, and her friend’s daughter a young woman with highly-active RRMS.

You may remember the other day I asked you to guess why I was so impressed with the HSCT-MIST trial. Let me try and explain why.

Should we be changing our expectations of what DMTs can offer pwMS? Are we entering an era when the expectation of disability improvement becomes the norm? I certainly hope so.

The most impressive aspect of the recent HSCT-MIST trial was not the NEDA data or the improved safety of HSCT, which are obviously important, but the disability improvement data. During the first year post-HSCT the mean EDSS scores improved from 3.4 to 2.4 vs. a worsening from 3.3 to 4.0 in those on the basket of licensed DMTs. Is this unique to HSCT? How does this HSCT data compare to other treatment options?

The first DMT to show a convincing impact on disability improvement in a phase 3 controlled trial was with natalizumab in the AFFIRM study; at 2 years the probability of a sustained improvement in disability was 30% for natalizumab-treated patients and 19% for patients who received placebo.

Phillips  et al. Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis. Mult Scler. 2011 Aug;17(8):970-9.

The next convincing phase 3 result was with alemtuzumab-treated patients in the CARE-MS2 trial; alemtuzumab-treated patients were more than twice as likely as IFN-β-1a-treated patients to experience 3-month confirmed disability improvement (35% vs 19%).

Giovannoni et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016 Nov 8;87(19):1985-1992.

Unfortunately, the latest HSCT trial did not report their disability improvement data as confirmed or sustained disability improvement at 3 months. The main reason for this was methodological in that patients patients on DMTs had a rescue option of being treated with HSCT. However, in the first 12 months, 12/55 (22%) of patients on DMTs compared to 38/55 (69%) who were treated with HSCT had an improvement in their EDSS. Based on the final data set I suspect that in a large proportion of the HSCT patients the improvements were sustained.

Burt et al.  Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. 2019 Jan 15;321(2):165-174.

What about the new kids on the block, i.e. ocrelizumab and cladribine? Unfortunately, we don’t have published data on cladribine, but I will try and rectify this and will ask for the analysis to be done. However, the phase 3 pooled OPERA data of ocrelizumab has been published; 21% of ocrelizumab-treated patients had disability improvement confirmed after at least 12 weeks compared to only 16% of  IFN-β-1a-treated patients.

Hauser et al. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-234.

So the league table for disability improvement of HSCT over alemtuzumab, over natalizumab, followed by ocrelizumab seems to mirror the brain atrophy or end-organ damage data. Are you surprised? I am not. A large driver of disability improvement is reserve capacity, i.e. brain reserve or put simply the size of your brain, which predicts and provides the substrate for recovery. This is another reason why you would want your MS treated early and just maybe you would want to flip the pyramid and go for the DMTs that offer you the best chance of disability improvement.

Hidden in this data may be a clue about the pathogenesis of MS. What differentiates HSCT and alemtuzumab from natalizumab and then from ocrelizumab? Could it be the transient depletion and reconstitution of the T-cell compartment?

Joanne Jones and her colleagues from Cambridge showed that among trial participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity on-trial, disability improved after alemtuzumab but not following interferon β-1a. They suggested that this disability improvement after alemtuzumab could not be attributable to its anti-inflammatory effects and suggested that T lymphocytes, reconstituting after alemtuzumab, permit or promote brain repair via the production of growth factors in particular brain-derived neurotrophic factor (BDNF),  platelet-derived growth factor (PDGF) and ciliary neurotrophic factor (CNTF). If their hypothesis holds out then this may be another reason why NIRTs (non-selective immune reconstitution therapies) outperform SIRTs (selective immune reconstitution therapies) in going beyond NEDA, i.e NEDADI. And just maybe you need these cells to traffic to the central nervous system to deliver these growth factors.

Jones et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain. 2010 Aug;133(Pt 8):2232-47.

Another piece of the puzzle is the positive effect alemtuzumab has on the MRI metric called magnetization transfer ratio or MTR, which is a measure of tissue integrity. In a small study, the mean MTR fell in 18 untreated MSers in normal-appearing grey and white matter. Conversely, mean MTR was stable in 20 alemtuzumab-treated MSers, which suggests alemtuzumab protects against tissue damage. This MTR data mirrors the clinical observations and is congruent with some of the basic science. Wouldn’t it be nice to do an experiment of using natalizumab post-alemtuzumab to see if by blocking T-cell trafficking we blunt the alemtuzumab-associated improvement in disability, i.e. to test whether T-cell trafficking is required to drive repair mechanisms?

Button et al. Magnetization transfer imaging in multiple sclerosis treated with alemtuzumab.  Mult Scler. 2013 Feb;19(2):241-4.

So what do I tell my patient? Do I tell her that the reason why she has not improved is that she is older, has more advanced MS and hence less reserve capacity to allow disability improvement? Or that we may not have tackled the root cause of her MS with subcutaneous cladribine? I stuck to the former explanation as the latter is simply a hypothesis that needs more thinking, more debate and some new experiments to establish if the treatment hierarchy in relation to end-organ damage and disability improvement is based on the different modes of action of our DMTs.

Despite the reasons behind these observations we are now entering an era were disability improvement is not an unreasonable expectation for pwMS, provided they are treated early and with high-efficacy DMTs.

How many you have been told about disability improvement on DMTs?

CoI: multiple, please note that I am a co-author on the natalizumab, alemtuzumab and ocrelizumab disability improvement papers.

Beyond NEDA

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