Lab Lessons – Page 16 – Prof G's MS Blog Archive

1st-line HSCT

If push came to shove would you really choose HSCT as a first-line treatment to treat your MS?

When asked on the blog yesterday which DMT would I choose if I had MS, I chose HSCT. One of my patients, who I have been looking after for over a decade, sent me an email stating how upset she was that I had never offered her HSCT. I clearly need to explain my position so as not to upset anyone else.

Firstly, HSCT is not on offer as a routine NHS therapy. At the moment HSCT is only considered as a 2nd or 3rd-line treatment in the most active patients. Another problem is that it is not on offer across the country. There are only a handful of MS centres that are prepared to refer their patients for HSCT. This means that access to HSCT is not equitable and explains why an increasing number of patients are having to travel abroad, at great personal cost, to receive this therapy. Inequity of care is against one of the founding principles of the NHS and is unacceptable.

The block in access to HSCT seems to be at the level of the neurologist/MSologist. NHS England guidelines for bone marrow transplant (BMT) units allows them to use up to 15% of their procedures to treat autoimmune conditions, which includes multiple sclerosis. As BMT units exist across the country access to these units would simply require a referral from a neurologist to the unit to perform HSCT on patients with MS. However, the latter is unlikely to happen unless the local MSologist champions HSCT as a procedure and gets their local haematology unit on board. It always takes a local champion to make things happen and our Barts-MS champion is Dr Ben Turner.

Another factor that has changed in the last 10 years is the strength of the evidence-base showing how effective HSCT really is as a treatment for MS. The most recent MIST trial, the first large randomised controlled trial, and several meta-analyses of HSCT, which have been extensively discussed on this blog, have confirmed that HSCT is a very effective therapy. At the same time the risks associated with HSCT have improved and the mortality in most BMT units is now below 1% for MS. This is now tipping the scales in favour of HSCT becoming a mainstream treatment for MS. There is however resistance from the MS community about HSCT been offered as a first-line therapy. Why? I suspect because the risk:benefit profile of HSCT has yet to be compared in a head-2-head study against our most effective licensed treatment. This why we are planning to do a head-2-head study of alemtuzumab vs. HSCT in the hope of generating this evidence. We know already that HSCT will be more cost-effective than alemtuzumab, but will it be more effective and as safe? Don’t try and second guess the results of this trial; I would not be surprised if there is no difference between these two treatments in terms of efficacy.

Please remember that most of the proponents of HSCT as a treatment for MS recognise that the major benefits from treatment will only be derived if HSCT is used early in the course of the disease. This explains why most BMT units don’t offer HSCT to pwMS with more advanced, or progressive, MS. However, this does not stop private, fee-for-service, units offering HSCT to all-comers. If you have the money and are willing to travel abroad you will be able to find a BMT unit that will treat you. I think this is wrong and will not happen in the NHS when HSCT eventually becomes widely available. We have to be honest with our patients about the risks and the benefits and why we will limit HSCT to those who benefit the most. In fact there is evidence that more advanced patients may actually be made worse by HSCT; the chemotherapy used to ablate the immune system is neurotoxic and may speed up neuronal loss. In addition, infections are common when you have HSCT and infections are well known to worsen MS disability in more advanced disease.

Please be aware that HSCT is not for the faint-hearted. It is a risky therapy with serious adverse events and quite a high mortality. Even a mortality rate of 0.3-0.5% is high when compared to other licensed DMTs. Should this stop us from offering HSCT first-line? I think not. If we are prepared to offer alemtuzumab, with its risk profile as a first-line treatment, why not HSCT? Most pwMS would agree that the decision regarding what is an acceptable risk to take should be taken by the patient and their families, and not the neurologist or other HCP. There is data showing that neurologists are much more risk-averse than pwMS. Neurologists need to acknowledge this bias, which is likely to be an unconscious bias, and let their patients make the decision.

What I am really trying to do by stating that if I had MS I would choose HSCT as my treatment is to reframe the DMT debate, particularly in relation to access to highly effective DMTs. By focusing on HSCT as a first-line treatment it should at least consider what your treatment objectives are in MS.

Framing is another a cognitive bias that was identified by Daniel Kahneman, the Nobel laureate, and his partner Amos Tversky. By moving the frame to the right, i.e to include HSCT as a 1st-line therapy, it makes it more likely for pwMS and their neurologists to choose more effective treatments. We now know that people who start on a low to moderate efficacy DMT do worse on average than those who start on a high or very high efficacy therapies do better. Despite this the majority of pwMS are not told this and are started on a low efficacy or platform DMTs without ever being given the option of a high efficacy DMT. Why? It is not due to lack of access to treatments as we now have several NICE and NHS England approved high efficacy DMTs available as first-line treatments.

So yes, if I had active MS I would want to have the full spectrum of high-efficacy DMTs available to choose from including HSCT. I would want to know about their relative efficacy and what the aim of the treatments are. I would certainly want to have a discussion about the possibility of a potential cure. Wouldn’t you?

By framing the spectrum of efficacy by having HSCT within the frame may nudge patients and their neurologists to move up the treatment ladder and choose a high efficacy DMT.

Unfortunately, HSCT as a first-line option is not going to happen any time soon, which is why I am trying to nudge the community to start debating the issue in earnest and why I want us to have a citizens jury on the issue.

Katerina Akassoglou

Did you enjoy ACTRIMS?

On Thursday evening I had the privilege of being at the Barancik Prize award ceremony and lecture. Katerina Akassoglou received the award for her work on the blood-brain barrier and fibrin as a pro-inflammatory agent of the innate immune system. Her lecture was a tour de force on what a single individual with dedication and focus can achieve. Well done.

I was particularly impressed that Katerina’s group is now translating this work into the clinic and is developing a class of drugs that recognises and blocks a cryptic or hidden binding site on fibrin. Why is this important? When the blood-brain-barrier gets disrupted and fibrinogen, a clotting protein, leaks into the brain and spinal cord and gets is converted into fibrin. As fibrin this cryptic site is exposed, which stimulates a receptor on microglia, called the integrin receptor Mac-1 (also called alpha(M)beta(2) or CD11b/CD18). This receptor activates microglia and causes them to become ‘hot’ like hot chilly peppers. These chilly peppers burn the tissue around them; the activated or hot microglia produce a large number of damaging molecules including reactive oxygen species, which are not good for the brain and spinal cord and cause loss of axons and neurons.

Importantly, the antibody that Katerina has developed blocks the fribrin-microglia interaction has the potential to treat many diseases inclusing Alzheimer’s disease.

The problem I see with this treatment strategy going forward is how to test in MS. Does it get compared to placebo? Does it get added on to existing DMTs? How do you design proof of biology trials? How do you design dose-finding phase 2 trials? And finally, how do you design a phase 3 trial? Do you need to use this treatment continuously or only during the early stages of inflammation? Is it a treatment that is best targeted to progressive MS?

I suspect more CSF biomarker work looking at activated microglia and macrophages, BBB leakage and fibrin formation needs to be done to provide the tools to test this drug in MS.

Despite these challenges, the award will raise awareness of this pathway and the science underpinning it. I suspect big pharma is already all over this pathway and we may see CNS penetrant small molecule inhibitors emerging. If this work translates into clinical practice there will be many more accolades and awards for Katerina.

Well done and thank you for a very inspirational lecture.

Akassoglou et al. Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol. 2018 Nov;19(11):1212-1223.

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer’s disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

Akassoglou et al. The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med. 2007 Mar 19;204(3):571-82.

Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 (alpha(M)beta(2), CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogen-Mac-1 interaction in fibrinogen-gamma(390-396A) knock-in mice or pharmacologically impeding fibrinogen-Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (gamma(377-395)) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogen-Mac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the gamma(377-395) fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation.

Flipping the pyramid

Was the concept of flipping the pyramid as a treatment strategy explained to you when you were started on a DMT?

For several years I have been arguing for adopting the concept of flipping the pyramid as a treatment strategy for MS. This is a treatment strategy developed by rheumatologists for treating rheumatoid arthritis with great success. In short, flipping the pyramid is using very high efficacy treatments first line. The other treatment strategies are watchful waiting, slow escalation or rapid escalation.

I kid you not that watchful waiting is still alive and kicking, but is less common now than it was a decade or so ago. The message is finally getting through that ‘active MS’ is a modifiable disease and should be treated. Please note my emphasis on ‘active MS’, we are unable to offer people with inactive MS DMTs nor should we, therefore, watchful waiting is entirely appropriate in this situation. The debate, however, is about how to define inactive MS and how hard should we interrogate patients to exclude smouldering MS?

The slow escalation strategy uses clinical monitoring to make a decision to change treatments or not and is probably still the norm in the UK. The main reason is a lack of resources, i.e. staff and MRI scanners to implement annual MRI monitoring. Rapid escalation is probably the most common option chosen by patients and neurologists in other high-income countries, however, frequent MRI monitoring which is costly remains a barrier in many parts of the world.

By maintenance-escalation, we mean starting low and escalating up a treatment ladder using MRI monitoring to assist decision making. We know from several real-life data sets and clinical trials that on average you do better if you start on either natalizumab, fingolimod, alemtuzumab, daclizumab or more recently ocrelizumab, compared to the lower efficacy platform therapies.

It is very reassuring to see the latest real-life data set from Wales showing how much better pwMS do when they have started an ‘early intensive therapy’ compared to a ‘moderate efficacy maintenance-escalation’ approach. The evidence is now overwhelmingly in favour of the former treatment approach.

The question is whether or not neurologists and HCPs will at least register these observations and start to offer their patients a choice between these two treatment approaches?

When we designed our treat-2-target NEDA trial to compare these two approaches, several years ago, these concepts were quite new. When the trials finally got funded we at Barts-MS declined to participate because we don’t think there is clinical equipoise anymore; in other words, we don’t think it is ethical to randomise patients to a maintenance-escalation arm of a study given the emerging evidence-base.

At Barts-MS we feel strongly that our patients are educated about the above issues and actively participate in the decisions about which treatments they are started on or switched to. This does not mean that we the neurologists are not involved. In some situations, we make the decisions for our patients or limit the choices available because of extenuating factors. We also offer patients the choice of allowing us to choose or recommend a specific treatment for them. Interestingly, with the rising complexity of treatment options many more patients are opting for the latter.

Paternalistic medicine, i.e when the doctor makes the decisions, is making a comeback but only this time as an informed choice

Many of the relevant issues I discuss above were covered in my ‘Hot Topics’ talk at ECTRIMS. I am going to suggest I do a Hangout on this topic to go through these in more detail and to allow you to ask questions. In particular, I need you to understand about the cognitive bias I refer to as the Gambler’s dilemma and how you need to try and overcome it when making decisions about your treatment.

For those of you reading this post and have been started on DMTs in the last 5 years was the concept of flipping the pyramid ever explained to you and the potential consequences, to you and your brain, if you chose the slower maintenance-escalation approach?

Harding et al. Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis. JAMA Neurol. 2019 Feb 18. doi: 10.1001/jamaneurol.2018.4905.

IMPORTANCE: Uncertainty remains about how aggressively to treat early multiple sclerosis. High-efficacy disease-modifying therapies (DMTs) are often reserved for individuals expressing poor prognostic features at baseline.

OBJECTIVE: To analyze long-term outcomes in a population-based cohort according to initial treatment strategy.

DESIGN, SETTING AND PARTICIPANTS: In this cohort study, data were derived from January 1998 to December 2016, and analysis was performed in January 2017. From a total of 720 patients prescribed a DMT, 592 (82%) were included in the analysis. Reasons for exclusion were first treated elsewhere or privately (n = 39), clinical trial participant (n = 25), and insufficient clinical data (n = 45).

EXPOSURES: Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]).

MAIN OUTCOMES AND MEASURES: Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD). Models were adjusted for sex, age at treatment, year of starting DMT, and escalation to high-efficacy treatment in the ESC group.

RESULTS: Mean (SD) age of 592 patients at symptom onset was 27.0 (9.4) years. Mean (SD) 5-year change in Expanded Disability Status Scale score was lower in the EIT group than the ESC group (0.3 [1.5] vs 1.2 [1.5]); this remained significant after adjustment for relevant covariates (β = -0.85; 95% CI, -1.38 to -0.32; P = .002). Median (95% CI) time to SAD was 6.0 (3.17-9.16) years for EIT and 3.14 (2.77-4.00) years for ESC (P = .05). For those within the ESC group who escalated to high-efficacy DMT as second-line treatment, median (95% CI) time to SAD was 3.3 years (1.8-5.6; compared with EIT group log-rank test P = .08). After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation.

CONCLUSIONS AND RELEVANCE: In a real-life setting, long-term outcomes were more favorable following early intensive therapy vs first-line moderate-efficacy DMT. Contemporary surveillance strategies and escalation protocols may be insufficiently responsive. This finding is particularly relevant as patients in real-world practice are typically selected for an EIT approach to therapy on the basis of clinical and radiological features predictive of a poor outcome. These data support the need for a prospective randomized clinical trial.

CoI: multiple

ADIOS

Yes, why can’t we use anti-CD20 therapies as an immune constitution therapy (IRT) or at least adapt the dose based on B-cell reconstitution kinetics? And if we can’t beat the Swedes why can’t we join them?

ADIOS = ADaptIve Ocrelizumab dosing Study

There is mounting evidence from NMO and rheumatology that anti-CD20 therapies can be used as either a maintenance therapy or an immune reconstitution therapy (IRT). Another way of using them is to adjust the dose based on memory B-cell reconstitution (MBR) kinetics.

Adapting the dose of anti-CD20 therapies using MBR or as IRT has appeal as it will almost certainly be safer in terms of infections, the emergence of hypogammaglobulinaemia and possibly the ability to respond to vaccines. It could also lead to better family planning by being able to expand the treatment-free period safely. Another plus would be cost-saving for the NHS and the other healthcare systems.

We are therefore in the process of designing a new trial to test standard interval dosing (SID) of ocrelizumab vs. adaptive dosing either using an MBR or an IRT protocol. What do you think? If you were on ocrelizumab would you sign up for this study? The advantage for you is that it may make your treatment safer in the long-term and it will potentially save the NHS millions.

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.

News for alemtuzumabers

Prof G what can be done to manage my hyperthyroidism if I want to fall pregnant?

Carbimazole is associated with an increased risk of congenital malformations, especially when administered in the first trimester of pregnancy and at high doses. Women of childbearing potential should use effective contraception during treatment with carbimazole.

Carbimazole: increased risk of congenital malformations; strengthened advice on contraception

As you know about 40% of women treated with alemtuzumab go onto to develop hyperthyroidism. The number one drug for controlling thyrotoxicosis is carbimazole. The fact that it is teratogenic is a problem as a lot of women with MS choose to be treated with alemtuzumab so that they can fall pregnant safely off a DMT.

Endocrinologists will have to rely on using propylthiouracil another oral medication that is used to manage hyperthyroidism. Although propylthiouracil may be given in pregnancy it crosses the placenta and in high doses may cause foetal goitre and hypothyroidism, therefore the lowest possible dose should be given and thyroid function monitored every 4-6 weeks to maintain optimum control. Propylthiouracil also transfers to breast milk but this does not necessarily preclude breastfeeding. Neonatal development and infant thyroid function should be closely monitored.

The management of MS gets more complex. I am becoming an endocrinologist in my spare time 😉

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.

EBV infects T-cells

Why are experts important?

In the so-called post-truth era experts are derided and ignored. Not at Barts-MS.

Last Friday we held a lock-in to review and discuss our EBV research programme and bring in expertise from outside our group. We were fortunate to have card-carrying EBV experts, oncologists, B-cell biologists and protein and antibody experts around the table. A central plank of the EBV hypothesis of MS has been built on the B-cell data, i.e. memory B-cells is one of the likely treatment targets for licensed DMTs and it just so happens to be the cell that EBV uses as its home. EBV hijacks the B-cell’s machinery and is so doing is likely to tip the balance towards autoimmunity. The dogma in the field is EBV is a B-cell tropic virus. I was therefore very surprised to hear new evidence which shows EBV also infects T-cells and therefore is likely to have an impact on T-cell biology. At the moment it is only the EBV type 2 that has been shown in infect T-cells, but this observation is likely to apply to the type 1 virus as well.

What does this mean for MS? I am not sure, but it has potential implications for how we target EBV in people with established MS; that is if EBV is the treatment target. At the very least it challenges some of our thinking about how we treat MS. For example, if we need to eliminate EBV to cure MS we probably have to target other compartments, including the T-cell compartment, and not just the B-cell and plasma cell compartments. T-cells may act as a reservoir for persistent EBV infection. This may explain why combined T- and B-cell depleters (non-selective immune reconstitution therapies), although riskier in the short-term, seem to have the edge over B-cell depleters when it comes to end-organ damage markers (brain volume loss) and confirmed disability improvement (CDI). NIRTs have also been described to eliminate EBV from the body in a small number of patients, which has not been described for B-cell depleters. It also means that we will need to build in components to our research programme that also focuses on T-cells as a potential mediator of EBV’s effects on the immune system.

Why are experts important? Experts teach you things you don’t know. Experts have the time and background knowledge to do the necessary deep thinking on their subject, which is required to challenge the prevailing dogma. I would like to thank the experts who came to our lock-in last Friday; you have changed my worldview on EBV.

Coleman et al. Epstein-Barr Virus Type 2 Infects T Cells in Healthy Kenyan Children. J Infect Dis. 2017 Sep 15;216(6):670-677.

BACKGROUND: The 2 strains of Epstein-Barr virus (EBV), EBV type 1 (EBV-1) and EBV-2, differ in latency genes, suggesting that they use distinct mechanisms to establish latency. We previously reported that EBV-2 infects T cells in vitro. In this study, we tested the possibility that EBV-2 infects T cells in vivo.

METHODS: Purified T-cell fractions isolated from children positive for EBV-1 or EBV-2 and their mothers were examined for the presence of EBV and for EBV type.

RESULTS: We detected EBV-2 in all T-cell samples obtained from EBV-2-infected children at 12 months of age, with some children retaining EBV-2-positive T cells through 24 months of age, suggesting that EBV-2 persists in T cells. We were unable to detect EBV-2 in T-cell samples from mothers but could detect EBV-2 in samples of their breast milk and saliva.

CONCLUSIONS: These data suggest that EBV-2 uses T cells as an additional latency reservoir but that, over time, the frequency of infected T cells may drop below detectable levels. Alternatively, EBV-2 may establish a prolonged transient infection in the T-cell compartment. Collectively, these novel findings demonstrate that EBV-2 infects T cells in vivo and suggest EBV-2 may use the T-cell compartment to establish latency.

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

Beyond the B-cell

Do we have the right cell target in MS? Yes and no; we need a multicellular approach.

Recently the attention in MS has been on the B-cell as if it was the holy grail of MS treatments. It is not.

In several posts, over the last few weeks, I have made the case that the B-cell is important, probably as an antigen presenting cell, but it is not the ‘be all and end all’ of MS treatments. It is clear that rebound post-natalizumab is driven my B-cells and the positive data on the first BTK inhibitor would indicate that the B-cells are working via the B-cell receptor on antigen presentation. If only we knew what these antigens were we would have a much better handle on the cause of MS.

I know this science stuff is hard, but it is important. At the end of the day, the nut and bolts of MS must be molecular; molecules mean treatment targets and potentially more focused and hopefully better and safer treatments in the future.

I have stressed that simply targeting B-cells in both the periphery and central nervous system will not be enough to effectively treat MS in the long-term. When we look at end-organ damage markers in pwMS who are on B-cell therapies they have ongoing brain volume loss, albeit at a lower rate, and enlarging lesions (T1 black holes), which are both indicative of ongoing smouldering MS. So what do we need to do? I have provided circumstantial evidence that NIRTs (non-selective immune reconstitution therapies) have a slight edge on the B-cell therapies and this may be because they are also targeting T-cells. The latter, however, comes at a price of greater adverse events in relation to immunosuppression. The proportion of MSers on NIRTs who experience disability improvement seems higher when compared to the anti-B cell agents, which indicates that NIRTs are doing something else over and above their effect on the B-cell compartment. However, based on their overall safety profile it is unlikely that the NIRTs (alemtuzumab & HSCT) will be a therapeutic strategy that the wider MS community will adopt with vigour. Although from comments on this blog there is an informed group of MSers who feel hard done by because their HCPs won’t offer them the option of using NIRTs first-line, i.e. very early in the course of their disease when they have the most to gain from these therapies.

Is there anything else we can do to improve on the profile of B-cell therapies to make them better? Yes, I think there is. Targeting the plasma cell,in addition to the B-cell. Data on plasma cells goes back decades and surprisingly the plasma cell has never been a major therapeutic target in MS. John Prineas, one of my MS heroes, has always stressed the importance of the plasma cell in MS. His paper below from 1978 documents just how enriched the brains of MSers are with this population of cells. What is often not stressed is that the biology of plasma cells is so so different to the B-cell, which opens up new therapeutic targets that are quite different to those in the T and B cell compartments. More on this topic another time.

You are aware of the recent publication showing that about 55% of Polish MSers treated with intravenous cladribine lost their oligoclonal bands 10 or more years after treatment and if they did lose their OCBs they tended to have lower EDSS scores. We have known for years that MSers, with either relapse-onset or primary progressive diseases, who don’t have OCBs do better. There is also evidence from biomarker and pathology studies that the OCBs may be driving several of the disease processes that have been linked to advanced or progressive MS, i.e. microglial activation and grey matter pathology. Based on these observations, we hypothesise that OCBs are very likely to be pathogenic in MS, which is why we are embarking a research programme to try and target the plasma cells within the CNS of MSers. Do you think we are crazy?

To get a handle on the plasma cell we are going to have to study what happens in the spinal fluid. There are simply too many plasma cells in the periphery which will drown out any signal from the CNS. To participate in the studies we are planning we will have to perform serial, annual, lumbar punctures or spinal taps to see if our add-on therapy is killing and/or reducing the number of plasma cells in your brain and spinal cords. The good news is that we have de-risked the lumbar puncture with the use of atraumatic needles and screening. I never thought I would be saying this but most of our patients don’t mind having LPs, particularly when they understand the reason behind the LP. CSF neurofilament levels are now part of our prognostic profile of MSers at baseline and we are increasingly using them to assess response, or lack of response, to treatment. So if you want to be treated and treated-2-target beyond NEDA, and beyond the B-cell, then having an LP is important.

We hope our proposed plasma cells studies will lead to a mindset that goes beyond the B-cell to target some of the mechanisms that are responsible for smouldering MS.

Prineas & Wright. Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest. 1978 Apr;38(4):409-21.

Perivascular cells in CNS tissue from six multiple sclerosis (MS) patients and a patient with motor neuron disease were examined by light and electron microscopy. Lymph node tissue from one MS patient was also examined. CNS perivascular macrophages in both MA and motor neuron disease were found to closely resemble free macrophages elsewhere in the body except that they often contained unusually large primary lysosomes. Cytoplasmic inclusions consisting of membrane-bound stacks of curved linear profiles, presumed to be a product of myelin degradation, were constantly observed in microglia in MS plaques but were rarely observed in perivascular macrophages in the same area. Unidentified cylindrical bodies were observed within cysternae of rough endoplasmic reticulum in some lymph node cells. Quantitative studies of the perivascular cell population in one MS case revealed, in histologically normal white matter 260 lymphocytes and 178 plasma cells per cubic millimeter of fresh tissue. Typical chronic plaque tissue without obvious inflammatory cell cuffing contained 1772 plasma cells per cubic millimeter of fresh tissue. No plasma cells were observed in the CNS in motor neuron disease. The results of this study suggest that perivascular macrophages in the CNS represent a specialized population of monocyte-derived free macrophages, that these cells differ functionally from microglial cells, and that the digestion of myelin breakdown products in MS requires the participation of both cell types. The results also suggest that in some chronic MS cases there is a large, permanent population of CNS plasma cells that persists, like the elevated cerebrospinal fluid IgG level in this disease, for the life of the patient, that these cells, rather than inflammatory cells in fresh lesions, are the major source of this raised IgG, and that the existence of such a population of cells may indicate the continuing expression of antigens in chronic MS lesions in the absence of fresh lesion formation.