Lab Lessons – Page 12 – Prof G's MS Blog Archive

Do no harm

Primum non-nocere is a Latin phrase that means “first, do no harm”.

On the tube this morning I recognised one of our medical students reading Henry Marsh’ book “Do no harm”. He is a semi-retired neurosurgeon, turned author, who uses his past patients to discuss ethical dilemmas and to criticise the NHS. His book does showcase the life of a surgeon, warts and all. It is clear that to be a good neurosurgeon you have to be a team player. In surgery, it is critical to get the clinical decision-making correct, i.e. when and when not to operate. Surgery is also a technical speciality above all else; from the age of about 55 a surgeon’s skills deteriorate so it is best to be operated on by someone who is in their prime. In short, if you make the wrong clinical decision and you get things wrong technically then you will get a suboptimal outcome; i.e. you will do harm.

I remember from very early on in my medical school career being told to do no harm. It is important to understand that this phrase dates back from a bygone era; an era when we hardly had any treatments that worked.

Wikipedia: It is often said that the exact phrase “First do no harm” is a part of the original Hippocratic oath. Although the phrase does not appear in the AD 245 version of the oath, similar intentions are vowed by, “I will abstain from all intentional wrong-doing and harm”. The phrase “primum non nocere” is believed to date from the 17th century. Another equivalent phrase is found in Epidemics, Book I, of the Hippocratic school: “Practice two things in your dealings with disease: either help or do not harm the patient”.The exact phrase is believed to have originated with the 19th-century English surgeon Thomas Inman.

In the modern era, we have to walk a tightrope of treating people to prevent future harm from a specific disease, knowing well that a small number of patients will be harmed from the side effects of the treatment. In other words, modern medicine has become a balancing act between the outcome of a population of patients at the expense of a small number of patients with adverse events.

In the MS space, natalizumab epitomises this dilemma. Natalizumab is one of our most effective DMTs; it is very effective, easy to use and has few adverse events, which are uncommon. Unfortunately, however, in JC virus-positive individuals it may result in PML a life-threatening infection of the brain. A lot has been done to derisk this complication, but unfortunately, there are still pwMS developing PML as a complication of natalizumab.

One industry analyst said to me that he had no idea why natalizumab was still on the market. He felt it should have been withdrawn after the PML crisis emerged. I said to this individual that he clearly hasn’t seen the impact that natalizumab has on people with MS’ lives. Natalizumab is a truly a transformative drug, which is why I refer to the treatment of MS as being represented by two eras; pre- and post-natalizumab.

It is clear that pwMS understand that to maximise outcomes for pwMS some individuals have to pay the price of suffering adverse events. This is why it is not surprising that pwMS are prepared to take greater risks than their risk-averse neurologists (see below). I recall working with a rheumatologist who made the point that if he didn’t have a few of his patients dying each year from the complications of his treatment decisions then he was not treating his patients actively enough. The corollary is that a rheumatologist without a body count is being too conservative.

Could the same analogy be levelled at neurologists? I think yes. I am still seeing far too many pwMS for second or third opinions who are very disabled from watchful waiting, slow escalation or sideways switching when they should have been treated with high efficacy treatments years ago. We really need to change the behaviour of MSologists from being risk-averse to becoming risk-takers. This also means pulling no punches and telling pwMS how bad MS really is and that to maximise your outcome you need to treat the disease effectively early on.

At Barts-MS we are taking this principle to the extreme with our #AttackMS trial. As always the ideas underpinning this trial are already being adopted by our team so that by the time we get the trial funded and up and running we may not be able to do the study because we would have lost equipoise.

Wikipedia: Clinical equipoise, also known as the principle of equipoise, provides an ethical basis for medical research that involves assigning patients to different treatment arms of a clinical trial. In short, clinical equipoise means that there is genuine uncertainty in the expert medical community over whether a treatment will be beneficial.

I would be interested to know the MS Community’s opinions on the #AttackMS trial.

Heesen et al. Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists. Mult Scler. 2010 Dec;16(12):1507-12.

BACKGROUND: Natalizumab is associated with the potentially life-threatening side-effect progressive multifocal leukoencephalopathy (PML). Little is known about patients’ and physicians’ risk estimates and attitudes towards natalizumab treatment.

METHODS: Consecutive natalizumab-treated patients (n = 69) and neurologists (n = 66) in two centres and cooperating private practices received an evidence-based three-page information leaflet about natalizumab-associated PML and an evaluation sheet.

RESULTS: After reading the information, patients were significantly more likely than physicians to intend continuation of natalizumab treatment and willing to accept higher risks of PML: 49% of physicians would stop treatment at a PML risk of 2:10,000 or lower, while only 17% of patients would do so (p < 0.001). This difference could not be explained by risk calculation abilities or lack of understanding. Both groups overestimated natalizumab treatment effects.

CONCLUSION: Patients had a significantly worse perception of multiple sclerosis as a malignant disease. We conclude that patients were willing to accept a higher risk of PML than neurologists. Coherent with their perception of risks and benefits, patients were also more willing to continue treatment. Open information about treatment-related risks is appreciated and might support shared decision making.

CoI: multiple

Air pollution and MS

We know that smoking, passive smoking and solvent exposure increase your risk of getting MS. The hypothesis, supported by animal work, suggests these risk factors alter antigens or proteins in the lung that then trigger autoimmunity. In other words, the altered proteins are interpreted as being foreign by the immune system.

Particulate air pollution is another respiratory toxin that has been studied in Iran and is associated with an increased prevalence of MS. I suspect that particulate matter air pollution also increases your risk of getting MS based on similar mechanisms to smoking and solvent exposure.

Another aspect of particulate matter air pollution exposure is that it drives comorbidities and is therefore likely to make MS progress more quickly. The second paper (below) in this week’s BMJ is quite shocking in that it shows you how high the health burden is for particulate air pollution, at a general population level. Is there anything we can do about this? Yes, there is. We need to nudge our politicians whenever we can to enact legislation to clean up the air that we have to breathe. I am aware that there are retrograde steps in the US to reverse some of the clean air legislation; this should be resisted. My heart goes out to people living in low- and middle-income countries who will have to wait for a generation or two to get to the point when air pollution drops to safer levels.

Why should people with MS be exposed to unnecessarily high levels of air pollution that are likely to make their MS worse?

Why should people at high risk of getting MS, be exposed to environmental pollutants that may push them over the “autoimmune tipping point” resulting in them developing MS?

Part of our lifestyle and wellness campaign is focusing on environmental health; air pollution is one of the things that impact wellness. Our marginal gains management philosophy has just acquired another component; environmental pollution. Do you agree?

Heydarpour et al. Potential impact of air pollution on multiple sclerosis in Tehran, Iran. Neuroepidemiology. 2014;43(3-4):233-8.

BACKGROUND: Multiple sclerosis (MS) incidence has dramatically increased in Tehran, Iran. The health impact of air pollution in Tehran underscores the attention to a possible association to this environmental risk factor. In this study, the authors aimed to analyze the spatial distribution of prevalent MS cases and their association with the spatial patterns of air pollution.

METHODS: Patient records meeting McDonald’s criteria for definite MS diagnosis with disease onset during 2003-2013 were obtained. Next, the location of 2,188 patients was successfully geo-referenced within Tehran metropolis by geographic information system (GIS) bureau of Iran’s post office based on their phone numbers. A cluster analysis was performed using the average nearest neighbor index (ANNI) and quadrat analysis. The long-term exposures of MS patients to particulate matter (PM10), sulfur dioxide (SO2), nitrogen oxide (NO), nitrogen dioxide (NO2), and nitrogen oxides (NOx) were estimated using the previously developed land use regression models.

RESULTS: Prevalent MS cases had a clustered pattern in Tehran. A significant difference in exposure to PM10, SO2, NO2, and NOx (p < 0.001) was observed in MS cases compared with controls.

CONCLUSION: This study revealed the potential role of long-term exposure to air pollutants as an environmental risk factor in MS.

Wei et al. Short term exposure to fine particulate matter and hospital admission risks and costs in the Medicare population: time stratified, case-crossover study. BMJ. 2019 Nov 27;367:l6258. doi: 10.1136/bmj.l6258.

OBJECTIVE: To assess risks and costs of hospital admission associated with short term exposure to fine particulate matter with diameter less than 2.5 µm (PM2.5) for 214 mutually exclusive disease groups.

DESIGN: Time stratified, case-crossover analyses with conditional logistic regressions adjusted for non-linear confounding effects of meteorological variables.

SETTING: Medicare inpatient hospital claims in the United States, 2000-12 (n=95 277 169).

PARTICIPANTS: All Medicare fee-for-service beneficiaries aged 65 or older admitted to hospital.

MAIN OUTCOME MEASURES: Risk of hospital admission, number of admissions, days in hospital, inpatient and post-acute care costs, and value of statistical life (that is, the economic value used to measure the cost of avoiding a death) due to the lives lost at discharge for 214 disease groups.

RESULTS: Positive associations between short term exposure to PM2.5 and risk of hospital admission were found for several prevalent but rarely studied diseases, such as septicemia, fluid and electrolyte disorders, and acute and unspecified renal failure. Positive associations were also found between risk of hospital admission and cardiovascular and respiratory diseases, Parkinson’s disease, diabetes, phlebitis, thrombophlebitis, and thromboembolism, confirming previously published results. These associations remained consistent when restricted to days with a daily PM2.5 concentration below the WHO air quality guideline for the 24 hour average exposure to PM2.5. For the rarely studied diseases, each 1 µg/m3 increase in short term PM2.5 was associated with an annual increase of 2050 hospital admissions (95% confidence interval 1914 to 2187 admissions), 12 216 days in hospital (11 358 to 13 075), US$31m (£24m, €28m; $29m to $34m) in inpatient and post-acute care costs, and $2.5bn ($2.0bn to $2.9bn) in value of statistical life. For diseases with a previously known association, each 1 µg/m3 increase in short term exposure to PM2.5 was associated with an annual increase of 3642 hospital admissions (3434 to 3851), 20 098 days in hospital (18 950 to 21 247), $69m ($65m to $73m) in inpatient and post-acute care costs, and $4.1bn ($3.5bn to $4.7bn) in value of statistical life.

CONCLUSIONS: New causes and previously identified causes of hospital admission associated with short term exposure to PM2.5 were found. These associations remained even at a daily PM2.5 concentration below the WHO 24 hour guideline. Substantial economic costs were linked to a small increase in short term PM2.5.

Brave dreams, or not

A blast from the past. Just when we thought CCSVI had died a quiet death the Brave Dreams trial is reported. It is clear that venoplasty in pwMS with “CCSVI”, a non-disease, are not cured of having MS.

However, it appears that venoplasty may have some weak antiinflammatory effects. A secondary assessment in subjects with favourable venograms had a significantly higher probability of being free of new cerebral lesions than patients with unfavourable venograms. The interesting question is how does stretching your veins have an anti-inflammatory effect in MS.

One hypothesis would be via the stimulation of the parasympathetic afferent or sensory nerve fibres that innervate cerebral veins and venous sinuses. There is an extensive literature on the potential mechanisms of how parasympathetic stimulation, using the vagal nerve, could be anti-inflammatory.

I suspect exploring the mechanisms of how venoplasty is anti-inflammatory is academic because the treatment effect is so small and is nowhere close to the effectiveness of licensed DMTs. Why would you have venoplasty if you could be on a more effective DMT?

I hope this will finally be the last we hear about CCSVI. I want to stress when you apply medical philosophical principles, CCSVI is not a disease; it does not fulfil the contemporary definition of being a disease entity. In short, there is not clinicopathological correlate that defines CCSVI as being a disease. A better descriptor for CCSVI would be that it is a meme.

Definition: A meme an image, video, piece of text, etc., that is copied and spread rapidly by Internet users, often with slight variations.

Zamboni, et al. for the Brave Dreams Research Group. Effects of Venous Angioplasty on Cerebral Lesions in Multiple Sclerosis: Expanded Analysis of the Brave Dreams Double-Blind, Sham-Controlled Randomized Trial. J Endovasc Ther 1526602819890110 2019 Nov 17.

Purpose: To evaluate if jugular vein flow restoration in various venographic defects indicative of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis (MS) patients can have positive effects on cerebral lesions identified using magnetic resonance imaging (MRI).

Materials and methods: The Brave Dreams trial ( ClinicalTrials.gov identifier NCT01371760) was a multicenter, randomized, parallel-group, double-blind, sham-controlled trial to assess the efficacy of jugular venoplasty in MS patients with CCSVI. Between August 2012 and March 2016, 130 patients (mean age 39.9±10.6 years; 81 women) with relapsing/remitting (n=115) or secondary/progressive (n=15) MS were randomized 2:1 to venography plus angioplasty (n=86) or venography (sham; n=44). Patients and study personnel (except the interventionist) were masked to treatment assignment. MRI data acquired at 6 and 12 months after randomization were compared to the preoperative scan for new and/or >30% enlargement of T2 lesions plus new gadolinium enhancement of pre-existing lesions. The relative risks (RR) with 95% confidence interval (CI) were estimated and compared. In a secondary assessment, venograms of patients who underwent venous angioplasty were graded as “favorable” (n=38) or “unfavorable” (n=30) for dilation according to the Giaquinta grading system by 4 investigators blinded to outcomes. These subgroups were also compared.

Results: Of the 130 patients enrolled, 125 (96%) completed the 12-month MRI follow-up. Analysis showed that the likelihood of being free of new cerebral lesions at 1 year was significantly higher after venoplasty compared to the sham group (RR 1.42, 95% CI 1.00 to 2.01, p=0.032). Patients with favorable venograms had a significantly higher probability of being free of new cerebral lesions than patients with unfavorable venograms (RR 1.82, 95% CI 1.17 to 2.83, p=0.005) or patients in the sham arm (RR 1.66, 95% CI 1.16 to 2.37, p=0.005).

Conclusion: Expanded analysis of the Brave Dreams data that included secondary/progressive MS patients in addition to the relapsing/remitting patients analyzed previously showed that venoplasty decreases new cerebral lesions at 1 year. The secondary analysis confirmed the efficacy of the Giaquinta grading system in selecting patients appropriate for venoplasty who were more likely to be free from the accumulation of new cerebral lesions at MRI.

Bonaz et al. Anti-inflammatory Properties of the Vagus Nerve: Potential Therapeutic Implications of Vagus Nerve Stimulation. J Physiol, 594 (20), 5781-5790 2016 Oct 15.

Brain and viscera interplay within the autonomic nervous system where the vagus nerve (VN), containing approximately 80% afferent and 20% efferent fibres, plays multiple key roles in the homeostatic regulations of visceral functions. Recent data have suggested the anti-inflammatory role of the VN. This vagal function is mediated through several pathways, some of them still debated. The first one is the anti-inflammatory hypothalamic-pituitary-adrenal axis which is stimulated by vagal afferent fibres and leads to the release of cortisol by the adrenal glands. The second one, called the cholinergic anti-inflammatory pathway, is mediated through vagal efferent fibres that synapse onto enteric neurons which release acetylcholine (ACh) at the synaptic junction with macrophages. ACh binds to α-7-nicotinic ACh receptors of those macrophages to inhibit the release of tumour necrosis (TNF)α, a pro-inflammatory cytokine. The last pathway is the splenic sympathetic anti-inflammatory pathway, where the VN stimulates the splenic sympathetic nerve. Norepinephrine (noradrenaline) released at the distal end of the splenic nerve links to the β2 adrenergic receptor of splenic lymphocytes that release ACh. Finally, ACh inhibits the release of TNFα by spleen macrophages through α-7-nicotinic ACh receptors. Understanding of these pathways is interesting from a therapeutic point of view, since they could be targeted in various ways to stimulate anti-inflammatory regulation in TNFα-related diseases such as inflammatory bowel disease and rheumatoid arthritis. Among others, VN stimulation, either as an invasive or non-invasive procedure, is becoming increasingly frequent and several clinical trials are ongoing to evaluate the potential effectiveness of this therapy to alleviate chronic inflammation.

CoI: nil

Participating in Oratorio-Hand?

At the recent ORATORIO-HAND investigators’ meetings in Barcelona and Athens, several investigators’ made the point that it may be hard to retain people with PPMS in this trial because ocrelizumab has already been licensed to treat MS. I said YES and NO.

For one a lot of neurologists, HCPs and payers don’t think the original ORATORIO trial was positive. They think the trial was driven by the 25% or so of the subjects with PPMS who had active disease, i.e. those with Gad-enhancing lesions at baseline. I have even heard some people claim that this trial was positive because it was contaminated by relapsing patients. This was not the case, all subjects had to have PPMS to get into this study. Any history of previous relapse excluded them from the trial. As a result of this doubt, many countries and insurance companies have not agreed to license or reimburse ocrelizumab for PPMS. To convince the naysayers, laggards and sceptics we need another PPMS trial to confirm the original results and extend the findings into pwPPSM with more advanced disease to show that ocrelizumab has a treatment effect in older and more disabled pwPPMS. This is why our age cutoff for the ORATORIO-HAND study is 65 and EDSS cut-off is 8.0 (wheelchair users). In the original ORATORIO study, these cutoffs were 55 years and EDSS of 6.5 (bilateral support, but still mobile).

Statisticians will tell you that when you only do one trial, which is positive, there is about a 1 in 20 to 40 (2.5% to 5%) chance that result could be positive by chance. In statistical jargon, this is referred to as a false-positive result or type 1 error. This is why the regulators usually require two positive trials to license a product; the first trial to test the hypothesis and the second to confirm the results of the first trial. If one trial is positive and the second trial is negative, or vice versa, this usually results in a third trial being required. This is what happened with laquinimod in RRMS; you may recall the third trial (CONCERTO) turning out to be negative so the laquinimod MS development programme was halted. Herein lies a hidden danger. If ORATORIO-HAND is negative and does not confirm a significant treatment effect in PPMS it could be used by regulatory authorities to question the result of the ORATORIO trial and potentially withdraw the license. A negative result will justify payers refusal to reimburse the costs of ocrelizumab to treat PPMS. I am confident this is not going to happen, but we need your help to makes sure this does not happen.

The ORATORIO-HAND is a very well-designed study and is adequately powered to give a positive result. The scientific principles underpinning this study are sound. However, if too many subjects drop-out to accept being treated with ocrelizumab when it is reimbursed in their countries or game the trial, i.e. find a way to unbind themselves, and drop-out this could potentially result in the study being underpowered, i.e. there are too few subjects to show a significant result when comparing placebo and active treatment groups. If this happens it could not only jeopardise treatment for themselves but the whole PPMS community. This is why I am appealing to all potential ORATORIO-HAND trial subjects if you are not sure about your longterm commitment to the trial you should not volunteer.

We are very aware that half the trial subjects will be allocated to placebo. Someone investigators asked why didn’t we make the randomisation 2:1, i.e. for every one person on placebo two people would be allocated ocrelizumab. The logic is that by having a 2-out-of-3 chance of being on active treatment the more likely pwPPMS are likely to volunteer for the study and to stay the distance. There are two reasons for the one-to-one randomisation ratio; time and possibly cost. Increasing the time it takes to recruit study participants is important. We estimate to recruit another 500 subjects, to allow a 2:1 ratio, would take another 12-15 months, which means we would be exposing a third of the subjects to placebo for an additional 12-15 months and potentially denying many pwPPMS across the world earlier access to the ocrelizumab. A 12-15 month extension to the recruitment phase means 12-15 month delay for drug getting to wider PPMS population. These are the factors that convinced the steering committee to choose the 1:1 randomisation ratio. Although cost is an obvious potential consideration we didn’t even ask senior management at Roche the question.

At the end of the day, we are asking pwPPMS to be altruistic. We are asking you to volunteer for a study and have a 50% chance of being randomised to a placebo knowing that ocrelizumab may be available to you as part of routine clinical practice or could become available to you during the trial. I know some people will ask does it have to be a randomised double-blind controlled trial? Could we generate the evidence in another way? The answer is no; the regulators will only change the label of ocrelizumab if the study is done to their standards. As you are aware it is virtually impossible to get a healthcare system-wide adoption of an MS treatment without a marketing authorisation from the appropriate regulatory body.

There are also other advantages to being in a trial. We don’t know why but trial participants tend to do better than non-trial participants even if you are randomised to placebo. This may relate to better care offered in a trial or participating in a trial has psychological benefits that can’t be quantified. I favour the latter explanation. There is evidence that people who have a purpose, a sense of belonging and are valued have better health outcomes than people without. Being a trial participant gives you a sense of purpose and being valued in that they are contributing the greater good. I have also noticed over the years that trial participation expands social capital; trial participants get to know the trial staff and other trial participants. I even know of two study subjects from one of the early trials who ended up marrying each other. Others have become friends and see each other outside the trial unit; I have bumped into two of trials participants in a local east curry house together. These intangibles can’t be quantified, but they definitely exist.

In countries in which ocrelizumab is not licensed or reimbursed for treating PPMS the advantages of participating in the ORATORIO-HAND study are obvious. But even in countries where ocrelizumab is reimbursed receiving it as part of a trial may help as well. Although we can’t pay for you to participate in the trial all of your out-of-pocket expenses related to travel will be covered.

I want to emphasise the positive of ORATORIO-HAND. For decades pwPPMS have felt neglected, ignored and left to smoulder away. Not anymore. The fact that the first ORATORIO trial was positive has shifted the goalposts and there will now be a flurry of PPMS trials. If ORATORIO-HAND fully recruits and is completed without too many dropouts the study will change the playing field for good. It will mean that PPMS is truly modifiable regardless of disease activity and potentially even people in wheelchairs will benefit. Getting a license for ocrelizumab in wheelchair users will affect the DMT stopping criteria, in other words even if you have to start using a wheelchair the treatment will have to be continued to preserve your arm and hand function. More importantly, it will get the whole MS community to say ‘Yes, we now agree that ocrelizumab works in PPMS’ and will allow pwPPMS across the world to access treatment.

We acknowledge that there are many legitimate reasons for why study subjects dropouts in clinical trials. We have factored this into the power calculations. What I am focusing on here is excess drop-outs over and above what we expect to occur from experience of other ocrelizumab trials.

This post is simply rehearsing some of the reasons for pwPPMS who volunteer for the ORATORIO-HAND study to stay the distance and complete the study. Please let me know if you agree, or disagree, with these points. I am also keen to find other reasons to help the many participating centres retain their patients in this trial.

CoI: multiple; importantly, I am the principal investigator on the ORATORIO-HAND study and I want to give this trial the maximum chance of being successful. Our #ThinkHand campaign will only be judged a success if and when we get a DMT licensed to protect upper limb and hand function in pwMS.

The Time-to-Think DMT

At an MS Masters Forum in Rome yesterday I was teaching MSologists and MS clinical nurse specialists using a recently created board game, which I like to think of as being MS Monopoly. MS monopoly is based on a game of chance that lets you discuss case scenarios and make treatment choices. Then you roll a dice, which determines the outcome of your choice.

Two things emerge from playing the game. Firstly, how choosing an immune reconstitution (IRT) addresses so many of the treatment aims and longterm issues of safety. The question I ask is why aren’t the IRTs dominating the treatment landscape?

Secondly, it became clear how many times natalizumab was considered as a treatment option and discarded because of its PML risk. From yesterday’s discussions it clear to me that natalizumab is the ‘time-to-think’ DMT, i.e. you start someone on natalizumab for 6-12 months whilst you make the necessary long-term decisions. This may be necessary to wait for lymphopaenia to recover, to complete a vaccination programme (e.g. the three-dose HPV polyvalent vaccine), to wait to get the all-clear on a previously-treated malignancy, to prevent rebound on stopping fingolimod so that the woman with MS can fall pregnant, or to complete a diagnostic work-up. The latter indication underpins our #AttackMS trial design.

Another indication for natalizumab is to prevent CNS adverse events associated with cancer immunotherapy. I recently recommended that a patient with MS who had disseminated bowel cancer and was about to start an immune checkpoint inhibitor go onto natalizumab despite being JCV positive to prevent exacerbation of her MS. The rationale being that the polyclonal activation of her T-cells in the periphery, including her autoimmune cells responsible for her MS, would not traffic to the brain and spinal cord and cause an MS relapse. The downside of this strategy is that if she had occult secondaries in her CNS then natalizumab will prevent her T-cells finding and clearing these cells. As bowel cancer rarely metastasizes to the CNS we thought this was a risk worth taking. Last I heard she was doing well from the MS perspective, but not that well in relation to her bowel cancer.

I am sure natalizumab will prevent the CNS complications associated with CAR-T cell therapies. Could this be a repurposing opportunity for natalizumab?

What makes natalizumab so uniquely special as a DMT are the observations that it has the most rapid onset of action of all the DMTs, it has very high efficacy, its mode of action can be reversed with plasma exchange and natalizumab does not cause systemic immunosuppression. The only downside of natalizumab therapy is the long-term PML and other CNS infection risk and the emerging CNS lymphoma risk. These are all due to reduced CNS immune surveillance. The fact that extended interval dosing (EID) reduces the PML risk by over 80% suggests natalizumab may make a resurgence and all these CNS side effects may be preventable. However, for this to happen we need to be able to prescribe natalizumab more liberally as a first-line treatment for active MS. If anyone from Biogen is reading this blog post can you please ask the powers that be in Biogen to consider asking the EMA to reconsider natalizumab’s label? By not doing this you are denying many pwMS access to natalizumab, albeit for a short period of time as highlighted above.

The good news is that the EMA has accepted the EID data and it is now in natalizumab’s summary of product characteristics.

New text in the EMA’s SmPC: In a pre-specified, retrospective analysis of US anti-JCV antibody-positive natalizumab patients (TOUCH registry), the risk of PML was compared between patients treated with the approved dosing interval and patients treated with extended interval dosing as identified in the last 18 months of exposure (EID, average dosing intervals of approximately 6 weeks). The majority (85%) of patients dosed with EID had received the approved dosing for ≥1 year prior to switching to EID. The interim analysis showed a lower risk of PML in patients treated with EID (hazard ratio = 0.06 95% CI of hazard ratio = 0.01- 0.22). The efficacy of natalizumab, when administered with EID, has not been established, and therefore the benefit/risk balance of EID is unknown (see section 4.4).

For those interested, I have included the latest PML figures from Biogen.

CoI: multiple

Rituximab combination therapy

A dark age is when society regresses; it goes backwards in time. The shocking revelations in last week’s New England of Journal of Medicine on the dire situation of some type 1 diabetics upset me and indicates we may be entering a dark age. An age when we are forcing our patients to turn their backs on innovation because they, or society, can’t afford to purchase the necessary medications to allow them to treat their disease.

“The price of insulin has risen to a level where some patients have reported rationing their medication, which has resulted in worsening glycemic control and, in some cases, diabetic ketoacidosis and death. Approximately 90% of insulin sold in the U.S. is manufactured by one of three companies (Eli Lilly, Novo Nordisk, and Sanofi). The rising cost of insulin in the United States can be attributed primarily to two phenomena. First, U.S. law allows pharmaceutical manufacturers to price their products at whatever level they believe the market will bear and to raise prices over time without limit. Second, direct competition in the insulin market is lacking.”

Excerpt from Michael Fralick & Kesselheim. The U.S. Insulin Crisis — Rationing a Lifesaving Medication Discovered in the 1920s. N Engl J Med 2019; 381:1793-1795.

I can only conclude that the politicians, with their neoliberal agenda, are failing these patients and society in general. The plight of type 1 diabetics is just the tip of the iceberg in a healthcare system that is being ripped apart by raw and unbridled capitalism. This is why the Labour party in Britain are warning us about the potential consequences for the NHS when we lose the protection of the EU post-Brexit.

Is the rationing of DMTs happening to people with MS? Several pwMS have commented on this blog how unaffordable DMTs are in the U.S. if you don’t have medical insurance and/or are covered by one of the socialist healthcare systems you are being forced to forego treatment. For me, as an academic working in MS, this is worrying because as we move into an era of combination therapies we are going to have to make combinations of treatments affordable. If one company controls all the components of the combination they can then price the therapy at an affordable price. However, if the components of the combination are controlled via different companies then the price of the individual components may make combination therapies too expensive.

We have been making the case of building a sandwich with a potent anti-inflammatory at the base and superimposing on top centrally acting anti-inflammatories, neuroprotective and remyelination therapies, neurorestorative treatments and anti-ageing agents. In addition to this, we may need a cocktail of drugs targeting comorbidities, either treating them or preventing them. As you can see the cost of treating MS will rapidly become prohibitively expensive.

In HIV Gilead tackled this problem by in-licensing different drugs from other companies to create their polypills. I envisage this happening in MS. If it doesn’t happen then the price of treating MS will beyond most people.

At the moment anti-CD20 therapies are rapidly becoming the base of the treatment pyramid, but the innovator anti-CD20 compounds are simply too expensive at present for competitors to use them as part of a combination therapy strategy. Even when ofatumumab and ublituximab get licensed for treating MS the cost of anti-CD20 therapies, in general, is unlikely to fall significantly. Maybe as part of our #AffordableDMT initiative, we can get wide adoption of rituximab biosimilars and use these more affordable anti-CD20 biosimilars at the base of the pyramid?

The problem we have is that rituximab is not licensed to treat MS. Outside of Sweden and the Kaiser Permanente in the U.S. systematic rituximab prescribing is patchy. Most HCPs are not confident enough to take on the risks of prescribing rituximab off-label. Even in Sweden the medical insurance company that covers Swedish neurologists in relation to their practice has said they won’t be able to cover their rituximab prescribing because of the extent of its use in Sweden. I am told that the Swedish government is having to create a bespoke medical insurance policy to cover system-wide off-label prescribing. Surely a better solution would be for the Swedish government to license rituximab as a treatment for relapsing MS and then this issue will go away?

If rituximab is licensed as a treatment for MS in Sweden then under reciprocal recognition rules in Europe we may be able to start using rituximab in the UK and other EU countries. This is assuming it happens before Brexit-related divorce laws disconnect us from Sweden and the EU. Another option would be for the NHS to license rituximab in the UK. I am not sure of the NHS has the will and/or the mechanisms for licensing a therapy for a specific disease, but it is something worth exploring. This would be a real game-changer both in the UK and internationally. This will allow us academics to at least build a combination therapy strategy with an affordable anti-CD20 at the base of the pyramid. This will allow us to test our induction-maintenance therapy hypothesis using generic drugs; for example, induction with rituximab followed by leflunomide as maintenance therapy.

Getting rituximab licensed to treat MS could be another strategic objective of our GRAD Initiative (Grass-Roots Affordable DMT Initiative). What do you think? This may appeal to low- and middle-income countries, particularly a country such as India that has a large and burgeoning biosimilars industry.

Please don’t be shy we need #AffordableDMT champions and wider engagement from the MS community. If you would like to get involved please get involved and register your interest. I would also like ideas from the wider community about how we get rituximab licensed as a treatment for MS. If you can’t beat Pharma you might as well join them 😉

CoI: multiple

Azathioprine revisited

Has azathioprine been given a fair chance as a treatment for MS?

I have noticed over the years that most neurologists, including myself, don’t always use azathioprine correctly. In general, we under-dose azathioprine. Why?

As an example, one of my patients with myasthenia gravis, an autoimmune disease of the nerve-muscle junction, came in this week with a relapse. He weighs 107kg and was on 200mg of azathioprine per day, which is less than 2mg/kg. He had a normal lymphocyte count. Therein lies the problem; his dose of azathioprine was too low, which is one of the reasons his myasthenia had broken through.

Azathioprine is a drug that is broken down by an enzyme called TPMT (thiopurine methyltransferase). There are genetic variants in TPMT which means you can be a slow, intermediate or rapid metaboliser of the drug. Before we start someone on azathioprine we test the activity of TPMT in their red blood cells and then adjust the target dose according to the enzyme activity. In general, we avoid using azathioprine in slow metabolizers as they can develop a low white cell count on very low doses. Intermediate metabolizers need a dose of 2-3mg/kg and rapid metabolizers a dose of 4-5mg/kg. This is a general guide and in practice, I titrate the dose upwards until I cause a mild lymphopaenia of between 0.8 and 1.2, whilst maintaining a normal neutrophil count.

As all the MS trials of azathioprine were done in the pre-TPMT enzyme activity monitoring era I looked up the azathioprine MS trials to see what doses were used. I was horrified to find out that except for one study all the other studies used a sub-therapeutic dose of azathioprine. In the Ellison 1989 trial, azathioprine was started at a daily dose of 2.2 mg/kg body weight, with the dose being increased by 25 mg each month until the white blood cell count was maintained between 3,000 to 4,000 or adverse effects were encountered. In this study, the daily dose was even increased above 4.4 mg/kg when appropriate. All the other studies used fixed-dose protocols with daily doses of azathioprine between 2mg/kg and 3mg/kg (2 mg/kg, Milanese 1993; 2.5 mg/kg, British & Dutch 1988, Ghezzi 1989; 3 mg/kg, Goodkin 1991).

What this is telling me that azathioprine has never really been trialled properly in MS and the fact that subtherapeutic doses seem to work is MS is quite remarkable (see Cochrane review below). This supports many old school neurologists anecdotal evidence that pwMS do better on azathioprine compared to patients, not on treatment. Maybe the WHO committee, who decide on the WHO Essential Medicines List, was right in telling us to reconsider our decision not to revisit azathioprine as a potential DMT for resource-poor countries.

One could argue in an era of treat-2-target and adaptive azathioprine dosing that we should relook at azathioprine as a cost-effective treatment for MS in resource-poor environments. We could start azathioprine at a low dose and titrate it slowly upwards to target a “therapeutic-dose” based on lymphocyte counts. We could then rebaseline and the monitor patients on a 6 or 12 monthly basis and only escalate therapy in patients who had breakthrough activity. I would not be surprised if azathioprine, under these circumstances, worked as well as our other platform therapies.

What do you think?

Barts-MS Essential Off-Label DMT List

*on the 19th WHO Model List of Essential Medicines (April 2015)

If you are interested in helping address the issue of lack of access to MS DMTs in resource-poor countries and environments please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI)

Casetta et al. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003982.

BACKGROUND: Azathioprine is the most widely used immunosuppressive treatment in multiple sclerosis (MS). It is an alternative to interferon beta for treating MS also because it is less expensive. Concerns about its safety, mainly a possible increased risk of malignancy, has limited its use. This systematic review aimed to determine the trade off between the benefits and risks of azathioprine in multiple sclerosis.

OBJECTIVES: To compare azathioprine versus placebo. To determine the effect of azathioprine on major clinical outcomes, i.e., disability progression and relapses in patients with multiple sclerosis.

SEARCH STRATEGY: The Multiple Sclerosis Group’s Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL- Issue 4, 2006), Cochrane Database of Systematic Reviews (CDSR – Issue 4, 2006), Database of Abstracts of Reviews of Effectiveness (DARE – searched 28.12.06) MEDLINE (PubMed) (1966 to December 2006), EMBASE (1980 to December 2006). Journals and reference lists were hand searched for relevant articles both to benefit and adverse effects. Regulatory agencies were additional sources of information for adverse effects.

SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing azathioprine treatment of a least one year duration with placebo for patients with multiple sclerosis. Cohorts, case controls, case series and case reports were also used to assess adverse effects.

DATA COLLECTION AND ANALYSIS: Potentially relevant references were evaluated and all data extracted by two independent authors.

MAIN RESULTS: The five trials that met our criteria included 698 randomised patients: data from 499 (71.5%) were available for analysis of relapse frequency in patients at one year’s, from 488 (70%) at two years’ and from 415 (59.5%) at three years’ follow-up. Azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR] =20%; 95% CI = 5% to 33%), at two years’ (RRR =23%; 95% CI = 12% to 33%) and three years’ (RRR =18%; 95% CI = 7% to 27%) follow-up. These results were consistent in sensitivity analysis. There was no heterogeneity among the studies. Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years. There was a statistically significant benefit (RRR = 42%; 95% CI = 7% to 64%) of azathioprine therapy at three years’ follow-up; this result was robust after sensitivity analyses and there was no heterogeneity among the trials. Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine group rather than in the placebo group; they were anticipated, and, by monitoring and dosage adjustment, were easily managed. Withdrawals due to adverse effects were few, occurring mostly during the first year of azathioprine treatment and mainly due to gastrointestinal intolerance (5%). Data from the trials and from cohort and case controls studies available in the literature did not show an increase in risk of malignancy from azathioprine. A possible long-term risk of cancer from azathioprine may be related to a treatment duration above ten years and cumulative doses above 600 g.

AUTHORS’ CONCLUSIONS: Azathioprine is an appropriate maintenance treatment for patients with multiple sclerosis who frequently relapse and require steroids. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy. Considering the trade off between the benefits and harms, azathioprine is a fair alternative to interferon beta for treating multiple sclerosis. A logical next step for future trials would seem the direct comparison of azathioprine and interferon beta. In fact the direct comparison between these two widely used treatments in multiple sclerosis has not been made.

CoI: multiple

Are IRTs ahead of their time?

I am beginning to think that immune reconstitution therapies or IRTs are ahead of their time. Many neurologists, people with MS (pwMS), payers – particularly fee-for-service insurance companies – and the regulators are unable to get their heads around how these agents work. In addition, a few recent review articles, written by colleagues, cast doubt on this treatment strategy and the terminology we use.

IRTs are the only treatments that are addressing the cause of MS and hence have the potential to cure MS. We will know in the near future how many pwMS in very long-term remission post -alemtuzumab, -HSCT or -cladribine are truly MS free. This information is critical to convince a sceptical field of the value of these treatments.

The mortality associated with HSCT makes people shudder. Although the risk of dying from one of the complications of HSCT is quoted as being between one of 1 in 333 (0.3%) to 1 in 50 (2%) many pwMS are taking this risk in the UK or abroad. Despite HSCT being a viable treatment option for pwMS in England and now Scotland many UK MSologists don’t routinely put this option on the table when discussing switching treatments with their patients who are failing other high-efficacy therapies. Why?

Even going to the easy-to-use, easy-to-monitor, oral cladribine option we are seeing slow adoption. Why? I am now convinced HCPs don’t understand IRTs, in particular, the concepts of frontloading of risk and long-term remission.

The study below shows that patients failing alemtuzumab in year one after the first course of five infusions, do very well after receiving their second course. Despite these patients having more active disease and early breakthrough activity, they do very well longterm with high chances of being rendered NEDA and experiencing disability improvement and having brain volume loss that slows markedly – into the normal range – after year 2.

DMTs are about protecting the end-organ or brain and keeping it as healthy as possible so that pwMS can live a normal life as possible and have the necessary reserve to deal with ageing when it sets in. Is this message difficulty to communicate? Knowing this brain volume data why wouldn’t we want to at least offer an IRT to all our patients with active disease and I mean first, second or third line? It is clear the sooner you are treated with an IRT the better you do.

I am now planning to do a series of online lectures on IRTs to explain why they should be so appealing as a treatment strategy for pwMS. Would you be interested in watching?

I also have a vested interest in getting IRTs adopted. We want to use them as induction agents in more advanced MS to be followed by maintenance therapies that target the processes within the brain and spinal cord to address smouldering MS.

Van Wijmeersch et al. Efficacy of alemtuzumab over 6 years in relapsing-remitting multiple sclerosis patients who relapsed between courses 1 and 2: Post hoc analysis of the CARE-MS studies. Mult Scler. 2019 Nov 1:1352458519881759

BACKGROUND: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen.

OBJECTIVE: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers).

METHODS: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension.

RESULTS: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%).

CONCLUSION: Early relapsers’ outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit.

CLINICALTRIALS.GOV REGISTRATION NUMBERS: CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.

CoI: multiple

De novo PML on ocrelizumab

In my career as a neurologist, I have seen three patients who developed PML (progressive multifocal leukoencephalopathy) without any apparent risk factors apart from being old. They were all over 70. Prior to the HIV epidemic, about 1 in 10 patients with PML did not have an obvious underlying risk factor except for age or immunosenescence of the elderly. Immunosenescence is the term immunologists use to describe malfunctioning of the immune system with ageing.

Based on the fact that even ‘normal’ elderly people have a very small risk of getting PML, it comes as no surprise that age is an emerging PML risk factor in MS, and explains why relatively safe DMTs have been associated with rare cases of PML. The last case of DMF-associated PML, who had a total lymphocyte count above 500, was in her sixties and old-age partially explains the first de novo case of PML on ocrelizumab (see below).

We received the notification from Roche today describing a case of PML in a patient treated with ocrelizumab as first-line therapy, who also had a mild lymphopaenia. The question you will be asking is why is a 76-year-old MSer being exposed to such a potent immunosuppressive agent? I don’t know. Maybe he had very active MS and his neurologist wanted to offer him a highly effective DMT first-line (flipping the pyramid).

As what has happened with alemtuzumab usage in the US we are likely to see a more severe and unexpected adverse event profile in MSers who are older on ocrelizumab. Being older means they are more likely to have comorbidities, immunosenescence and less biological reserve to deal with serious and life-threatening infections.

Am I concerned about this case? Yes and no. Yes, in the sense that I would think twice about using such a potent immunosuppressive agent in an elderly person with MS. No, in that de novo PML is rare with anti-CD20 treatment and is highly unlikely to be a problem in younger people with MS.

On reflection, cladribine would have been a better high-efficacy DMT for this patient. The fact that cladribine is a selective IRT (immune reconstitution therapy) and does not cause longterm immunosuppression makes it a safer agent in this population group. Unfortunately, when this patient was started on ocrelizumab oral cladribine was not licensed in the US and the current FDA label discourages first-line use of oral cladribine. So even if cladribine was available at the time it is unlikely that it would have been prescribed. An interesting topic that is emerging in the field is the management of MS in the elderly, including the management of highly-active MS in this population group. Maybe we should put this topic forward for one of our future triMS.online conferences?

ROCHE STATEMENT

In the interest of patient safety, and as part of our ongoing commitment to transparency, I am forwarding this information.

We are aware of a report of a confounded case of progressive multifocal leukoencephalopathy (PML) in a multiple sclerosis (MS) patient in the United States of America who was treated with Ocrevus^®▼(ocrelizumab). The potential contribution of Ocrevus treatment to this PML case is difficult to quantify but cannot be ruled out.
The patient has a long-standing history of MS. They were previously untreated and hence Ocrevus was their first disease-modifying therapy (DMT). The patient was treated with Ocrevus for two years, with the initiation of treatment in July 2017 and the last dose was administered in February 2019.
The treating physician has reported this as a confounded case of PML. Contributing factors (confounders) reported by the physician are the patient’s age (78) with potential immunosenescence, low absolute lymphocyte count (ALC) prior to treatment with Ocrevus (max CTCAE grade 1, no subtypes available), as well as low ALC (max grade 2), low CD4+ (max grade 2) and low CD8+ counts during treatment, with Ocrevus as a probable contributor.
Roche follow the American Academy of Neurology (AAN) criteria to establish the diagnosis of PML, in addition to consultation with an external advisory panel of experts.
Patient safety is Roche’s highest priority, and, consistent with our safety reporting processes, we report to health authorities in accordance with standard pharmacovigilance processes.
Roche is in contact with the treating physician to help evaluate the case, providing support and expertise where appropriate.
The overall benefit/risk for Ocrevus remains unchanged at this time. As of 30th September 2019, more than 130,000 people with MS have been treated with Ocrevus globally (1). To date, there have been no unconfounded cases of PML reported in patients treated with Ocrevus. All seven previous confirmed PML cases of patients treated with Ocrevus were confounded by and attributed to the previous DMT (carry-over cases). This is the first PML case in a patient treated with Ocrevus where the cause of the PML, although confounded, has not been attributed to a previous DMT.

The recommendations relating to PML in the approved product labelling for Ocrevus remain unchanged. Physicians should be vigilant for early signs and symptoms of PML, which can include any new-onset, or worsening of neurological signs or symptoms, as these can be similar to an MS relapse. If PML is suspected, withhold dosing with Ocrevus.

Please refer to the summary of product characteristics for full prescribing information here.

For ease of reference, we have collated an overview of all confirmed PML cases to date (October 2019):

Confirmed case no.	Country	Reported	Setting	Confounding factor(s)
1	Germany	May 2017	Compassionate Use programme	Prior DMT (Natalizumab)
2	Canada	April 2018	Post-marketing	Prior DMT (Fingolimod)
3	USA	May 2018	Post-marketing	Prior DMT (Natalizumab)
4	USA	June 2018	Post-marketing	Prior DMT (Natalizumab)
5	USA	July 2018	Post-marketing	Prior DMT (Natalizumab)
6	Luxembourg	September 2018	Post-marketing	Prior DMT (Natalizumab)
7	USA	February 2019	Post-marketing	Prior DMT (Natalizumab)
8	USA	October 2019	Post-marketing	Age (78) & low lymphocyte counts prior to, and during Tx

Mills and Mao-Draayer. Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients. Mult Scler. 2018 Jul;24(8):1014-1022. doi: 10.1177/1352458518775550.

New potent immunomodulatory therapies for multiple sclerosis (MS) are associated with increased risk for progressive multifocal leukoencephalopathy (PML). It is unclear why a subset of treated patients develops PML, but patient age has emerged as an important risk factor. PML is caused by the JC virus and aging is associated with immune senescence, which increases susceptibility to infection. With the goal of improving PML risk stratification, we here describe the lymphocyte changes that occur with disease-modifying therapies (DMTs) associated with high or moderate risk toward PML in MS patients, how these changes compare to immune aging, and which measures best correlate with risk. We reviewed studies examining how these therapies alter patient immune profiles, which revealed the induction of changes to lymphocyte number and/or function that resemble immunosenescence. Therefore, the immunosuppressive activity of these MS DMTs may be enhanced in the context of an immune system that is already exhibiting features of senescence.

CoI: multiple

My ‘Smouldering MS Clinic’

I finished yesterday emotionally burnt-out; “broken and useless, no longer working or effective” or “kaput” as the Germans would say. I did an all-day clinic with my registrar off sick; it was hard and brutal.

On my way home I wondered to myself if I should change the name of my MS clinic to the ‘Smouldering MS Clinic’. Virtually all of my patients had smouldering MS or as some of you would prefer me to call it PIRA (progression independent of relapses).

With our aggressive campaigns of treat-early-and-effectively, treat-2-target, zero-tolerance, NEDA (no evident disease activity) I think we have exposed the real MS, i.e. smouldering disease. Almost all my follow-up patients were NEDA yesterday and doing ‘well’. However, when I interrogated them almost all of them had subtle symptoms and signs of disease worsening. Worsening fatigue, cognitive slowing, reduced walking distance, dropped feet on exertion, nocturia, sexual dysfunction, numbness and clumsiness of the hand, subtle unsteadiness of gait, poor balance in the dark and when tired, increased leg spasms at night, reduced auditory discrimination, problems with night vision, etc.

The new norm is smouldering MS or more likely the realisation that MS is smouldering MS. Our anti-inflammatory DMTs are doing what we say they should do, i.e. they are stopping focal inflammatory lesions and relapses, but are they getting to the core of the disease, ‘smouldering MS’? I suspect not.

I have argued several times before on this blog that focal inflammation is not MS and that the real disease is what is driving the immune system to produce the focal inflammatory events. I suspect that effective DMTs are simply converting relapsing-forms of MS into what we used to call primary progressive MS.

If you have MS this post will be very depressing, but as soon as the MS community faces up to the above the better. We would then start directing our limited resources to tackle smouldering MS.

I would encourage the funders (government, charitable, private and pharma) to start to divert their R&D spend to addressing smouldering MS. What needs to be done? I would encourage out-of-the-box thinking and support alternative hypotheses of MS. We need deep phenotyping and biomarker studies. More trials on drugs targeting CNS B-cells and plasma cells, microglia inhibitors or activators (both need to be tested), drugs that target astrocyte and oligodendrocyte biology, antiviral trials and trials targeting ageing mechanisms. I would also include systems biology and the impact of diet, etc. on smouldering disease. We need a “Smouldering MS March of Dimes” event to raise the money to get on top of the real MS.

I would like to thank you all for helping out with our grant naming survey. It is clear that from a scientific perspective PIRA (progression independent of relapses) won out. However, smouldering MS came a close second and most commentators prefer this name to describe PIRA to people with MS and their families, i.e. smouldering MS is a lay-term for PIRA. I, therefore, suggest we keep both names in the MS lexicon and use them interchangeably when discussing the real MS.

Don’t be fooled into a false sense of security that because you are NEDA that your MS is under control. We clearly need to go beyond NEDA to tackle MS.

CoI: multiple