SELs – Prof G's MS Blog Archive

Smouldering MS – not all bad news

Barts-MS rose-tinted-odometer: ★★★★★ (today’s colour is Delta Red Iron Oxide #9b2f1c)

One of the smouldering MS dogmas that have entered the MS lexicon is that the iron-rimmed slowly expanding MS lesions (SELs) go on enlarging and destroying or shredding the brain tissue around it forever. Another dogma states these SELs don’t respond to current DMTs. The good news is that both of these statements are probably incorrect.

In the recently published longitudinal MRI study below iron rims around lesions gradually diminished with time. However, having these iron rim lesions is not good news in that they are significantly more destructive than non-iron rimmed MS lesions. The question I have is what drives these lesions to form? Knowing the answer to this question will tell us what is causing MS.

The second study below demonstrates that ocrelizumab significantly reduces the expansion of slowly expanding/evolving lesions. This suggests that these lesions may be driven by intrathecal or CNS-derived immunoglobulins. This is why we are doing the high-dose ocrelizumab, SIZOMUS (ixazomib) and CHARIOT-MS (cladribine) studies to see if reducing intrathecal B and plasma cell activity has an impact on smouldering MS.

If the former studies are positive, who would want to go onto a lower-dose anti-CD20 therapy (standard-dose ocrelizumab, ofatumumab, rituximab, ublituximab)? Please note that although these lower dose anti-CD20 therapies are very effective at stopping relapses and focal MRI activity this is not MS. The real MS is smouldering MS and what we see with end-organ damage markers. This is why if I had MS I would choose a DMT that offered the best chance of normalising my brain volume loss and I would volunteer for the SIZOMUS trial.

The good news is that these two studies below show that the so-called chronic active lesions or SELs evolve over many years after their initial formation and that they may be modifiable with DMTs. Let’s celebrate these facts.

Iron-rimmed lesion of SEL expanding over 7 years; image from BRAIN.

Dal-Bianco et al. Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI. Brain. 2021 Apr 12;144(3):833-847.

Recent data suggest that multiple sclerosis white matter lesions surrounded by a rim of iron containing microglia, termed iron rim lesions, signify patients with more severe disease course and a propensity to develop progressive multiple sclerosis. So far, however, little is known regarding the dynamics of iron rim lesions over long-time follow-up. In a prospective longitudinal cohort study in 33 patients (17 females; 30 relapsing-remitting, three secondary progressive multiple sclerosis; median age 36.6 years (18.6-62.6), we characterized the evolution of iron rim lesions by MRI at 7 T with annual scanning. The longest follow-up was 7 years in a subgroup of eight patients. Median and mean observation periods were 1 (0-7) and 2.9 (±2.6) years, respectively. Images were acquired using a fluid-attenuated inversion recovery sequence fused with iron-sensitive MRI phase data, termed FLAIR-SWI, as well as a magnetization prepared two rapid acquisition gradient echoes, termed MP2RAGE. Volumes and T1 relaxation times of lesions with and without iron rims were assessed by manual segmentation. The pathological substrates of periplaque signal changes outside the iron rims were corroborated by targeted histological analysis on 17 post-mortem cases (10 females; two relapsing-remitting, 13 secondary progressive and two primary progressive multiple sclerosis; median age 66 years (34-88), four of them with available post-mortem 7 T MRI data. We observed 16 nascent iron rim lesions, which mainly formed in relapsing-remitting multiple sclerosis. Iron rim lesion fraction was significantly higher in relapsing-remitting than progressive disease (17.8 versus 7.2%; P < 0.001). In secondary progressive multiple sclerosis only, iron rim lesions showed significantly different volume dynamics (P < 0.034) compared with non-rim lesions, which significantly shrank with time in both relapsing-remitting (P < 0.001) and secondary progressive multiple sclerosis (P < 0.004). The iron rims themselves gradually diminished with time (P < 0.008). Compared with relapsing-remitting multiple sclerosis, iron rim lesions in secondary progressive multiple sclerosis were significantly more destructive than non-iron rim lesions (P < 0.001), reflected by prolonged lesional T1 relaxation times and by progressively increasing changes ascribed to secondary axonal degeneration in the periplaque white matter. Our study for the first time shows that chronic active lesions in multiple sclerosis patients evolve over many years after their initial formation. The dynamics of iron rim lesions thus provide one explanation for progressive brain damage and disability accrual in patients. Their systematic recording might become useful as a tool for predicting disease progression and monitoring treatment in progressive multiple sclerosis.

Ocrelizumab reduces the increase in the volume of SELs compared to placebo; image from BRAIN.

Elliott et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. Brain. 2019 Sep 1;142(9):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.

Conflicts of Interest

MS-Selfie Newsletter / MS-Selfie Microsite

Preventive Neurology

Twitter / LinkedIn / Medium

General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

How soon does the shredder begin to shred?

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

She was only 26-years and she couldn’t understand why she was falling behind her peers at work. She started working at an ultra-competitive law firm after finishing as one at the top of her peer group at Oxford. She was clearly the best-performing intern in the 2017 intake, which is why she was kept on after her internship. However, things were now going wrong. She was suffering from chronic fatigue, forgetfulness and she simply couldn’t juggle the complex tasks she was being expected to working for more than one client at a time. This job was a high-octane one and you were expected to perform at the level. Her poor performance and increasing list of mistakes had resulted in one performance review already. What should she do?

The back story to this young lawyer is her identical twin sister had been diagnosed with MS at the age of 18, shortly after completing her A-levels. Her sister had decided to delay going to university because of being diagnosed with MS. The odds are this young lawyer had asymptomatic MS and her fatigue and cognition problems are linked to smouldering MS. Do you think she should seek a neurological opinion? She is aware that her lifetime risk of being diagnosed with MS is about 30%.

Do you think she should seek a neurological opinion?

I have made the case that the real MS is not relapses and/or focal MRI activity, but smouldering MS. The real question is when do the pathological processes that drive smouldering MS begin? In this study on asymptomatic MS (radiologically-isolated syndrome or RIS) a third of them already have cognitive impairment and two-thirds had lesions with paramagnetic rims (PRL), i.e. a rim of hot microglia. These so-called PRLs are the precursor to the dreaded SELs (slowly-expanding lesions) that are so unresponsive to our current treatments and responsible for so much damage in MS.

So what are the implications of this study for MS?

MS begins long before your first attack.
Smouldering MS, formerly known as progressive MS, also begins long before your first attack.
PRLs and SELs, one of the substrates for smouldering MS, are part of MS pathology from very early in the disease course; possibly the beginning.
Cognitive impairment and end-organ damage begin very early in the course of MS.
We need to change our diagnostic criteria to allow MS to be diagnosed very early on, in this case in the so-called asymptomatic phase of the disease. By using PRLs and the central vein sign (CVS) we are likely to improve the sensitivity and specificity of the diagnostic criteria. So what are we waiting for?

We clearly need a new treatment paradigm to tackle smouldering MS. The current anti-inflammatory monotherapy model of treating MS is unlikely to work. We need combination therapies ASAP. To achieve the latter we are going to have to get Big Pharma and the regulators to innovate quickly and intelligently.

Oh et al. Cognitive impairment, the central vein sign, and paramagnetic rim lesions in RIS. Mult Scler. 2021 Mar 23:13524585211002097.

Objective: The central vein sign (CVS) and “paramagnetic rim lesions” (PRL) are emerging imaging biomarkers in multiple sclerosis (MS) reflecting perivenular demyelination and chronic, smoldering inflammation. The objective of this study was to assess relationships between cognitive impairment (CI) and the CVS and PRL in radiologically isolated syndrome (RIS).

Methods: Twenty-seven adults with RIS underwent 3.0 T MRI of the brain and cervical spinal cord (SC) and cognitive assessment using the minimal assessment of cognitive function in MS battery. The CVS and PRL were assessed in white-matter lesions (WMLs) on T2*-weighted segmented echo-planar magnitude and phase images. Multivariable linear regression evaluated relationships between CI and MRI measures.

Results: Global CI was present in 9 (33%) participants with processing speed and visual memory most frequently affected. Most participants (93%) had ⩾ 40% CVS + WML (a threshold distinguishing MS from other WM disorders); 63% demonstrated PRL. Linear regression revealed that CVS + WML predicted performance on verbal memory(β =-0.024, p = 0.03) while PRL predicted performance on verbal memory (β = -0.040, p = 0.04) and processing speed (β = -0.039, p = 0.03).

Conclusions: CI is common in RIS and is associated with markers of perivenular demyelination and chronic inflammation in WML, such as CVS + WML and PRL. A prospective follow-up of this cohort will ascertain the importance of CI, CVS, and PRL as risk factors for conversion from RIS to MS.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

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.

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.
Rituximab has come off patent and several cheap biosimilars are now entering the market.
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

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.
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.
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.
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.
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.
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.

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 HAVE POPPIES AND FIELDS GOT TO DO WITH THE CAUSE OF MS?

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