Tag: slowly-expanding lesions

Smouldering MS: Is 20 years a long time?

Barts-MS rose-tinted-odometer: zero stars or one ★ depending on your disposition

I prepared this post not knowing that Prof. Laura Airas has submitted a guest post in response to a request from the Mouse Doctor. Before reading this post please make sure you read her blog post first. It provides an important counterbalance to my contrarian view below. Thank you.

More than 20 years ago, when I was a junior researcher, doing my PhD,  I started a research collaboration with Dr Richard Banati, who worked in the Queen Square Brain Bank and the Imperial College PET imaging unit. Richard was investigating activated microglia in multiple sclerosis. The collaboration was very fruitful and led to the very first study of an imaging molecule called PK11195  that could label activated microglia. 

In the study (see below), we elegantly showed that people with MS (pwMS) had widespread microglial activation in their brains. Their brains, in fact, lit up like Christmas trees with so-called ‘hot’ or activated microglia. The assumption, which is now dogma, from this and other studies is that these microglia must be bad for pwMS. This has led to many research and drug discovery programmes to find treatments to switch off hot microglia.   

PK11195 labelling hot microglia. From Banati et al.

Now dial forward 20 years and finally, a follow-up study from Finland that shows that pwMS with a lit Christmas tree in their heads do worse in the longterm, i.e. pwMS with more microglial activation as determined by PK11195 staining had more disease progression that was independent of relapses. The implication is that PK11195 is a good marker of smouldering MS and if we switch off this marker we will improve long-term outcomes. 

In an email exchange with colleagues, I challenged this thinking. Is the PK11195 signal, or hot microglial response, the chicken or the egg? The microglial response may not be causal but simply associated with a worse outcome in MS. Just maybe the microglia are responding to what is causing MS and are not the primary drivers of the MS pathology. Therefore if you switch off the microglial response you may not improve MS outcomes but actually make them worse. 

I even provided some early odds of this happening. I predicted that a drug that switches off the microglial response had only about a 20% chance of improving MS outcomes. I balanced this by saying that I thought that a microglial inhibitor had about a 60% chance of actually making MS worse. I was then challenged that these odds were simply a guess; like an unskilled poker player. I disagree. Firstly, poker is a game of skill and the most skilled poker players make a relatively decent living from their skills. Secondly, there is a scientific process behind making accurate predictions (see post-script), which I try to apply. Finally, we need to apply science to the microglial prediction at hand. 

The Science: In the smouldering or slowly expanding MS lesion the hot microglia are lined up like soldiers fighting an enemy at the edge of the lesion. They remind me of a Greek phalanx.

A Military Phalanx

These microglia are not malignant cells, which makes me think they are simply doing their job. Now what if these microglia are responding to something in the surrounding tissue, for example, a slow viral infection? Switching them off may actually make the slow viral infection worse. In addition, microglia have very important function clearing up debris in the nervous system and maintaining the health of synapses and neurons in general. 

Figure 1 (from Frischer et al., Ann Neurol 2015): (A, B) Early active plaques (EAL) were defined by macrophages immunoreactive for minor myelin proteins (MOG positive macrophages right insert in A) as well as major myelin proteins (PLP positive macrophages left insert in A). (C, D) Smoldering plaques (also called slowly expanding plaques) typically showed a rather inactive centre with no or few macrophages, surrounded by a rim of activated microglia. Only few of these macrophages or microglia cells contained early myelin degradation products. Inserts depict plaque edge. (E, F) Inactive plaques revealed a sharp plaque border without or only few macrophages or activated microglia (insert). (G, H) Completely remyelinated plaques typically containing few macrophages without early myelin degradation products were classified as shadow plaques. Shadow plaques presented with a sharp plaque edge and were associated with fibrillary gliosis.

More Science: Importantly, defects in the signalling pathway of CSF-1 (colony-stimulating factor 1), which is also known as macrophage colony-stimulating factor (M-CSF), cause progressive dementia and disease of the cerebral white matter called a leukoencephalopathy. CSF-1 is a microglial stimulant. This is a warning that inhibiting microglia indiscriminately is unlikely to be good for the brain and particularly a damaged MS brain. This is why I have given greater odds to a microglial inhibitor making MS worse than making MS better. 

I am also aware that there are different types of microglia, different types of microglial responses and hence we may have to be more selective in how we target microglia in MS. Despite this, I think we as an MS community need to take a step back and challenge the current dogma that the microglial response in MS is necessarily bad. If we don’t we may be unpleasantly surprised and disappointed with the outcome of clinical trials targeting hot microglia and smouldering MS. 

P.S. If you are interested in reading about the science of prediction I would recommend ‘Superforecasting: The Art and Science of Prediction’ by Dan Gardner and Philip Tetlock; a remarkable book that provides important insights and lessons to avoid unconscious biases and it teaches you a little poker as well 😉 

Sucksdorff et al. Brain TSPO-PET predicts later disease progression independent of relapses in multiple sclerosis.  Brain, awaa275, https://doi.org/10.1093/brain/awaa275 Published: 02 October 2020.

Overactivation of microglia is associated with most neurodegenerative diseases. In this study we examined whether PET-measurable innate immune cell activation predicts multiple sclerosis disease progression. Activation of microglia/macrophages was measured using the 18-kDa translocator protein (TSPO)-binding radioligand 11C-PK11195 and PET imaging in 69 patients with multiple sclerosis and 18 age- and sex-matched healthy controls. Radioligand binding was evaluated as the distribution volume ratio from dynamic PET images. Conventional MRI and disability measurements using the Expanded Disability Status Scale were performed for patients at baseline and 4.1 ± 1.9 (mean ± standard deviation) years later. Fifty-one (74%) of the patients were free of relapses during the follow-up period. Patients had increased activation of innate immune cells in the normal-appearing white matter and in the thalamus compared to the healthy control group (P = 0.033 and P = 0.003, respectively, Wilcoxon). Forward-type stepwise logistic regression was used to assess the best variables predicting disease progression. Baseline innate immune cell activation in the normal-appearing white matter was a significant predictor of later progression when the entire multiple sclerosis cohort was assessed [odds ratio (OR) = 4.26; P = 0.048]. In the patient subgroup free of relapses there was an association between macrophage/microglia activation in the perilesional normal-appearing white matter and disease progression (OR = 4.57; P = 0.013). None of the conventional MRI parameters measured at baseline associated with later progression. Our results strongly suggest that innate immune cell activation contributes to the diffuse neural damage leading to multiple sclerosis disease progression independent of relapses.

Banati, …., Giovannoni,….et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000 Nov;123 ( Pt 11):2321-37. doi: 10.1093/brain/123.11.2321.

This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [(3)H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [(3)H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [(3)H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [(3)H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [(11)C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T(1)- and T(2)-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [(11)C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

What is MS?

The more I read,  think and assimilate information the more I realise that the real pathology behind MS is not the new acute lesion or relapse, but what is going on behind the scenes in the so-called slowly expanding chronic MS lesion or SEL. 

MS is a smouldering disease. 

In an analysis of the ocrelizumab-PPMS or ORATORIO trial, it is clear that SELs already existed in the brains of PPMSers when they started the trial and best predicted their clinical course during the trial. In contrast, brain atrophy or brain volume loss and new lesion activity did not predict disability progression. What is nice about this analysis is that it is in a PPMS population with a very low relapse rate, which excludes relapses as a confounder. 

I am not that concerned about brain volume loss not predicting outcome in this population, because it is out of sync with clinical outcomes; i.e. brain volume loss today is caused by pathology 2-3 years ago and hence needs to be correlated with clinical outcomes in the past. 

What is important in this study is that new MRI activity in the form of new T2 lesions did not predict disability worsening. In other words, focal inflammation is not associated with clinical outcome. In comparison, SELs or smouldering MS predicted clinical outcome. Based on basic medical philosophical principles around the definition of surrogate markers it is clear that new T2 lesions can’t be the disease we call MS, but SELs can. 

It is clear to me that MS is a biological disease and not an MRIscopic disease, i.e. what you see on MRI is the tip, of the tip, of the iceberg and that most of MS pathology is hidden from view when using conventional MRI. This is why you still deteriorate despite being NEDA (with no evident new disease activity). The NEDA in this context is referring to the absence of focal MS inflammatory activity, i.e. relapse(s) and new or enlarging lesions on MRI. The biology behind the worsening despite being NEDA is driven by the delayed neuroaxonal loss from previous damage, ongoing diffuse inflammation which has become independent of focal lesions (innate activation), ageing mechanisms or focal inflammatory lesions that are too small to be detected with our monitoring tools. Of all the processes listed here, the last one is the only one that is realistically modifiable by our current DMTs. 

The really important question this analysis raises is that when you treat someone with a DMT and they become NEDA how do you know they don’t have ongoing smouldering MS and hence would benefit from being escalated to a more effective DMT or should be included in add-on combination therapy trial? This is why we need to start using end-organ damage markers and more sensitive inflammatory markers to look for and define smouldering MS. Only then will we be able to start answering important questions. For example, does changing treatment in people with smouldering MS to more effective DMTs, for example, natalizumab, alemtuzumab or ocrelizumab result in them doing better? The ORATORIO analysis below would suggest the treatment effect in this situation is small. This is why we are going to need a new generation of add-on treatments that target CNS pathology, for example, hot microglia, antivirals (EBV and HERVs), CNS-penetrant anti-B-cell and plasma cell agents, neuroprotectives, etc. 

I have made the point that primary progressive MS (PPMS) is simply smouldering RRMS and that all we are doing with our DMTs is converting people with RRMS to PPMS and delaying the inevitable progressive phase of the disease.  I don’t buy this because a proportion of pwMS who have been treated early on with an immune reconstitution therapy or IRT, in particular, alemtuzumab or HSCT, appear to be in very longterm remission and may even be cured of their MS (see the previous post on this topic). Some would argue, I included, that this group of patients has not been followed up for long enough to be sure they have been cured. I agree and this is why we need a deep phenotyping study to assess whether or not these patients have any evidence of ongoing MS disease activity. This study would help define smouldering MS, by looking for its absence. 

The MRI-centric view of MS has lulled many of us into a false sense of security and has resulted in us classifying MS as a focal inflammatory autoimmune disease of the CNS. In reality, MS is a diffuse disease of the CNS and the focal inflammatory events are simply the immune response to what causes MS. This is why the field hypothesis of MS is so relevant and fundamentally challenges our worldview of MS. 

If we don’t change our worldview of MS and explore what is happening in the trenches alongside the one we currently have our heads buried in we will be letting down the next generation of MSers. 

Image from ‘when is a paradigm shift required‘.

Elliott et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. BRAIN 2019: 142; 2787–2799. 

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/ evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1- weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

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.

What to do about my haloes?

Why do MS lesions with an iron halo continue to expand?

The slowly expanding MS lesion or SEL is where the money or lack of money is. In my post ‘explaining why you are getting worse despite being NEDA‘ I mention SELs as one of the reasons that underlie progressive MS and are largely unresponsive or poorly responsive, to standard DMTs.

Danny Reich’s team at the NIH have convincingly showed how these lesions differ from other lesions that regress over time. The expanding lesions have a rim of macrophages/microglia on their edges that are actively phagocytosing, or eating, myelin. These lesions are characterised by a prolonged rim of Gd-enhancement and dark rim on MRI that occurs due to an accumulation of iron in macrophages/microglia. These lesions are very destructive and leave behind a black-hole on MRI; the so-called Swiss cheese brain.

SELs and black-holes are associated with more axonal loss. The pathological study below shows that these lesions are not found (or rarely found) around remyelinated shadow plaques. Iron rims were due to pro-inflammatory activated microglia/macrophages and only very rarely in astrocytes. 

An important observation is that these lesions don’t seem to have prominent lymphocytes infiltrates; it is as if the macrophages/microglia in these lesions have become independent of adaptive (T and B cells) inflammation. Are these microglia dysregulated or are they responding appropriately to something in the surrounding tissue. One of the current hypotheses is that progressive MS is due to ‘hot microglia‘; the chronic expanding lesion may be the substrate for how microglia lead to progressive MS. Could SELs be the real disease?

Some have suggested these microglia are responding to the immunoglobulin that has bound to myelin or other components in the issue. Some have suggested the microglia are activated to clear up myelin that is being damaged by other mechanisms, for example, from viral or toxic factors.

SELs are found very early in the course of MS, even in the asymptomatic phase of MS or RIS (radiologically isolated syndrome) and a SEL forms in a strategic location it can drive worsening of disability in one pathway, such as progressive weakness of one side of the body (hemiplegia).

DMTs reduce the development of new SELs but have minimal impact on established SELs. This is another reason why we need to treat MS early and effectively. Clearly, to address SELs we will need to do a lot more research and develop new CNS-penetrant drugs that target the pathogenic mechanisms that are driving the expansion of these lesions. This may include add-on drugs to scrub the CNS clean of plasma cells, i.e. the cells that are producing the abnormal immunoglobulins, antivirals to switch off the causative virus or drugs that switch off macrophages/microglia. I am a little sceptical about the latter approach; I truly believe the microglia and macrophages are simply doing their jobs and are responding to the cause of the disease.

Dal-Bianco et al. Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging. Acta Neuropathol. 2016 Oct 27.

Background: In multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims. In susceptibility-based magnetic resonance imaging at 7 T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions. 

Aims: We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate iron and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7 T magnetic resonance imaging (MRI), and (4) if lesions with rims enlarge over time in vivo, when compared to lesions without rims.   

Methods: Double-hemispheric brain sections of 28 MS cases were stained for iron, myelin, and microglia/macrophages. Prior to histology, 4 of these 28 cases were imaged at 7 T using post-mortem susceptibility-weighted imaging. In vivo, seven MS patients underwent annual neurological examinations and 7 T MRI for 3.5 years, using a fluid attenuated inversion recovery/susceptibility-weighted imaging fusion sequence.   

Results: Pathologically, we found iron rims around slowly expanding and some inactive lesions but hardly around remyelinated shadow plaques. Iron in rims was mainly present in microglia/macrophages with a pro-inflammatory activation status, but only very rarely in astrocytes. Histological validation of post-mortem susceptibility-weighted imaging revealed a quantitative threshold of iron-laden microglia when a rim was visible. Slowly expanding lesions significantly exceeded this threshold, when compared with inactive lesions (p = 0.003).   

Conclusions: We show for the first time that rim lesions significantly expanded in vivo after 3.5 years, compared to lesions without rims (p = 0.003). Thus, slow expansion of MS lesions with rims, which reflects chronic lesion activity, may, in the future, become an MRI marker for disease activity in MS.

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

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