Please help I am getting worse

Barts-MS rose-tinted-odometer: ★

After my clinic last week I was emotionally drained and probably more than usual. Patient after patient was telling me the same story and asking the same questions.

“Since lockdown last year things have gotten worse, what can I do about it?”

My superficial interpretation is that most of these patients had gotten worse because of relative physical and mental inactivity. Working from home or not working, self-isolation to prevent getting COVID-19 and less physical exercise are taking their toll. I am increasingly making the point that unless you use it you will lose it (#UseItOrLoseIt). Put simply less physical exercise (self-isolation), less mental exercise (reduced work or no work) and less emotional exercise (social interactions) are having a devastating impact on people with MS. Then there is the shredder, i.e. ongoing MS disease activity be it new focal inflammatory lesions or the dreaded smouldering MS. As we have not been able to monitor pwMS with regular MRIs and change and escalate treatments a large number of pwMS are paying the price of having their MS undertreated.

One of the patients I spoke to via a video consult wanted to know why she was getting worse and why she was not eligible for siponimod treatment. She had not had a relapse in over 10 years and had no new lesions when we imaged her last year January 2020. She has gone from EDSS 6.0, i.e. being able to walk several hundred metres with a cane, to being wheelchair-bound in just 12 months. This rapidity of her secondary progression is faster than what we usually see. Most people spend at least 3 to 4 years at EDSS 6.0 and EDSS 6.5. The question I have is there be another reason for the rapid progression? Had she developed a new lesion in the spinal cord? The only way to sort this out is with an MRI and possible lumbar puncture and CSF analysis to measure neurofilament levels. The problem we have is that we are not doing non-urgent MRIs or lumbar punctures at present. However, I suspect the repeat MRI and CSF analysis will show no obvious new inflammation, which will make her ineligble for siponimod.

Many of these patients don’t understand that beyond relapses and focal MRI activity the real MS lurks. I explain why disease worsening or disability progression occurs in MS under 4 headings:

1. SS (scissors and stripper): The acute focal inflammatory lesion acts like molecular scissors and strippers, cutting axons and stripping myelin off axons. The cut and naked axons are blocked from conducting signals and result in a neurological deficit. The neurological deficit from this acute conduction block will vary depending on the pathway affected, for example, if the lesions affect the optic nerves it will cause loss of vision. The way to prevent the SS from causing conduction block is to prevent new lesions from forming. If this patient has a new lesion it would offer her hope and make her eligible for siponimod.

2. EF (energy failure): The demyelinated axons may recover function by a process called axonal plasticity or remyelination. Axonal plasticity is the process by which the neuron inserts new ion channels into the demyelinated axonal segments and restores conduction. Remyelination may also occur, but the new myelin is never as thick and as efficient as the old myelin and is susceptible to intermittent failure. These demyelinated and thinly remyelinated sections of axons are susceptible to temperature and fatigue. If the temperature rises these sections block and if the axons are used too much, for example with exercise, they run out of energy and also block. Sometimes the type of ion channel that is inserted into the axons fire spontaneously can cause intermittent symptoms, for example, pins and needles, pain, neuralgia and muscle spasms. As these ion channels are sodium channels it explains why these intermittent symptoms respond to drugs that block sodium channels, for example, carbamazepine, oxcarbazepine, phenytoin and lamotrigine.

I suspect a large amount of progressive disability in this patient is due to these mechanisms; sadly, we don’t have any add-on treatments we can offer her at present.

Another process that helps with recovery is that the surviving axons form sprouts to reconnect disconnected pathways and create new synapses, which are the connections between nerve fibres. All these processes increase the energy requirements of the axon, which makes it vulnerable to die-off later. At the same time the ‘MS lesion’ remains inflamed and some of the chemicals produced as part of the inflammation poison the mitochondria, which are energy factories of the axons. A further reduction in energy production puts further stress on the system. As a result of these processes, there is a delayed dying off of axons that takes place over months to years after the initial MS lesion has formed. This delayed dying off of axons explains why despite effective treatments stopping new MS lesions from forming some people with MS still notice a slow deterioration in their functioning. This is why we have added this patient to our prescreening log for the upcoming Chariot-MS trial in which we will be testing whether or not oral cladribine will slow down the worsening of upper limb function.

There is mounting evidence that exercise encourages plasticity, i.e. axonal plasticity and sprouting and synaptogenesis and recovery or maintenance of function. Sadly due to lockdown this patient had not been having physiotherapy and was unable to attend her regular aqua aerobics. Could she be losing function because of this? I suspect this could explain some of her deterioration.

3. SB (slow burn): Some MS lesions never recover and become slowly expanding lesions or SELs. SELs have a rim of hot microglia at their edges and continue to swallow up the myelin and axons of the surrounding ‘normal-appearing’ tissue. These lesions don’t have much acute inflammation left in them, i.e. there are very little T and B cells in these lesions. SELs continue to expand over years to decades and are responsible for the slow accumulation of damage over many years. SELs can be seen on MRI; they typically cause black holes on so-called T1-weighted MR images and have a dark rim of iron around them when viewed with special MR sequences (susceptibility imaging). The iron rim is a marker of these so-called ‘hot microglia’.

I would not be surprised if this patient had a SEL in a critical position in her cervical spinal cord. At present we have no idea what causes some MS lesions to regress and recover and for others to expand and become SELs. What we do know is that our standard anti-inflammatory DMTs have very little or no effect on SELs once they have developed. It is important to realise that SELs are found throughout the course of MS and are even seen in people with a radiologically isolated syndrome (RIS) or asymptomatic MS. In other words, the so-called ‘progressive MS pathology’ is found very early in the MS disease course. We do know that the number and size of the SELs increase with disease duration, i.e. the more MS lesions that develop the more SELs will be formed. Another important observation that has recently emerged is that a single strategically located SEL can cause an extraordinary amount of damage; for example, a single SEL in the so-called pyramidal tract or motor pathway can cause progressive weakness down one side of the body. I have a few patients like this and it is very disheartening when their weakness fails to respond to standard anti-inflammatory therapies.

An interesting debate is whether or not the ‘hot microglial’ response is abnormal, i.e. pathological, or is occurring in response to something in the surrounding tissue. I support the latter view and hypothesise that there is something in the surrounding tissue that is activating the microglia and they are just doing their job and trying to clear-up the inciting agent. Others have suggested these microglia are responding to the back-end, or Fc-end, of antibodies and activated complement components as a result of these antibodies reacting with their target or in a non-specific manner. Other hypotheses include viruses, e.g. EBV and HERVs, are driving the expansion of these lesions. The way to test these two competing hypotheses is to use drugs that switch off or suppress microglia. If the ‘hot microglia’ are the problem these drugs will work and stop SELs getting bigger. If the microglia are just doing their ‘job’ these agents are unlikely to work. It is also important to remind you that myelin debris inhibits remyelination so these microglia may be needed to help with the repair. The problem is that without being able to switch off the abnormal processes that are causing SELs to enlarge trying to stimulate repair mechanisms may be futile.

Another factor that can’t be ignored is recurrent infections, which sometimes affects a lot of people with advanced MS. Recurrent urinary tract infections (UTIs) are the biggest problem. This is why we take UTIs so seriously. Every time you get an infection it causes your immune system to produce cytokines, or inflammatory messengers, that travel to the brain and boosts the activity of the microglia. The hot microglia then exacerbate the damage that MS is doing to your brain and spinal cord. This is why many of you tolerate infections so poorly and often don’t recover back to baseline after a severe infection. There is a lot we can do to reduce recurrent bladder infections. For example, the judicious use of intermittent self-catheterisation, drinking lots of liquids to flush the bladder, using urinary antiseptics to suppress the growth of bacteria in the bladder and screening for asymptomatic UTIs using self-monitoring home dipsticking and prompt treatment.

This patient has had several UTIs in the last 12 months. To manage this I recommended she starts taking daily urinary antiseptics and she starts self-monitoring her urine twice weekly with dipstix and to start antibiotics ASAP as she picks up an early UTI. I hope the GP will do what I recommend; not all GPs are prepared to allow their patients to self-monitor and manage their bladders in this way.

The upshot of ‘slow burn’ is that we need additional therapies to add on top of DMTs that stop new lesions, and in particular chronic expanding or SELs, from forming. These treatments may be drugs to purge the CNS of antibody-producing B cells and plasma cells, drugs that inhibit complement activation and/or the activation of Fc receptors on microglia, anti-virals that target EBV and HERVs, and/or drugs that inhibit activated microglia. In other words, there are many therapeutic targets that still need to be explored as add-on therapies in MS.

4. PA (premature ageing): Most of you are aware of the effects of ageing on the nervous system. The brain and spinal cord were never designed by evolution to last longer than about 35 years. It is only relatively recently that as a species we have extended our lifespans. Once you go beyond approximately 35 years of age there is a gradual loss of nerve cells and axons. This explains why as you get older you notice the effects of ageing; reduced vision, loss of hearing, poor balance and sadly age-related cognitive impairment. In short, life is an age-dependent neurodegenerative disease. If we all live long enough we will all develop cognitive impairment. What protects us from age-related changes is so-called brain reserve capacity, i.e. the size of the brain and spinal cord, and cognitive reserve, which relates to education level and environmental enrichment (social capital, adult learning, cognitive exercises, etc.). We know that MS reduces both brain and cognitive reserve and as a result people with MS experience the impact of ageing much earlier. I refer to this as premature ageing. Can we do anything about this? Yes, we can. We know from studies in the general population there are many things that you can do to maximise your brain and cognitive reserve. This is called Brain Health and involves lifestyle factors such as exercise, diet, sleep and avoiding smoking and excessive alcohol consumption. It is also important to be screened for comorbidities or other diseases and have them treated; these include smoking, hypertension, diabetes, obesity and abnormal lipids. As for diet, there have not been any that have been studied specifically in MS. However, data from animal and other studies indicate that calorie restricted, intermittent fasting and ketogenic diets have the most promise with regard to brain health. However, we need more evidence of their beneficial effects before promoting these to pwMS.

Yes, this patient is in late 50’s and ageing mechanisms are clearly contributing her loss of function.

Ageing is also a biological process and as we decode the molecular programmes that cause ageing we may be able to develop treatments that reverse ageing. An example of this is metformin, a drug for treating diabetes that has recently been shown to reprogramme oligodendrocyte precursors in older animals to behave as if they were young cells and become more efficient at remyelinating axons. I envisage in the future using anti-ageing drugs as add-on therapies to treat MS.

At the moment we don’t have enough evidence to recommend an add-on treatment for this patient. However, trials are happening so maybe in the next decade of so we will have add-on treatments to slow down or reverse these premature ageing mechanisms.

Finally, we know from other diseases that mood and other social determinants affect outcomes in other diseases and likely play a role in MS. This patient was clearly socially-isolated and depressed. The social-isolation was self-inflicted due to her anxiety about getting COVID-19. Now that she has been vaccinated and with national cases numbers falling she start to get-out and meeting her family and friend again. I suspect she will improve, maybe not back to her pre-COVID-19 baseline, once she starts exercising and reconnencting with the world.

Does this patient’s story sound familiar to you? Have you managed to cope with the lockdown? What have you done to keep going?

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

Progressive multiple sclerosis is a misnomer

Barts-MS rose-tinted-odometer: ★

In my opinion, the term ‘progressive multiple sclerosis’ is a misnomer. In general, progression means improvement, which is one of the reasons I prefer the term ‘late-stage MS’, which not only differentiates the terminologies but captures the associated disability that comes with this phase of the disease.

It is important to stress that the pathologies that drive neuroaxonal loss, or neurodegeneration (the pathological substrate that underlies ‘late-stage MS’) are there from the earliest stages of MS; even when people have asymptomatic MS. This means the neurodegenerative phase of MS is present prior to pwMS becoming physically disabled.

MS is 1-disease and not 2-3-or-4-diseases. As I have said before the false division of MS into several diseases is not backed up by science, nor by philosophical arguments. This false division of MS into many diseases has become counter-productive to the field of MS. The division of MS into relapsing and progressive forms was Pharma-led to get MS defined as an orphan disease, which allowed interferon-beta-1b to get a license based on the results of one pivotal phase 3 study.

One could argue that this has been good for MS in that it has attracted a lot of Pharma investment and has supercharged drug development in MS. However, MS as three or four disease entities is now slowing down drug development and making it very expensive. We need more affordable DMTs for late-stage MS; disability affects the cost-effectiveness models for reimbursement hence DMTs for late-stage MS need to be priced lower than those licensed for earlier or relapsing forms of MS.

Following on the point above the division between SPMS and PPMS is false. There is no pathological, genetic, imaging or other data that suggests these are different entities. We therefore should be doing trials in both late-stage MS populations simultaneously.

Slay the dogma that more late-stage MS has reduced inflammation or is non-inflammatory. There are clinical, imaging and pathological data that shows inflammation plays a big part in driving late-stage MS. Therefore not to target more late-stage MS with an anti-inflammatory is folly.

Accept that reserve capacity in particular systems plays an important part in how MS worsens. Neuronal systems with reserve, i.e. surviving and functioning axons, are more likely to be able to recover function and hence show a treatment effect compared to neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; we refer to this as therapeutic-lag. These observations are explained by the length-dependent axonopathy hypothesis. This means that we will need to focus more on arm-and-hand function as a primary outcome in pwMS who have lost too much function in their lower limbs (EDSS>=6.0).

Challenge the dogma that once someone has lost lower limb function and is a wheelchair user that the disease is not modifiable. We have good data that DMTs can slow the worsening of upper limb function despite subjects being wheelchair-bound. We feel very strongly about this point and are very keen that future trials in late-stage MS include wheelchair users. Why should we write-off people with MS who have lost leg function? What keeps pwMS independent and functioning in society is arm and hand function. We as a community have to think about that very carefully. We have rehearsed these arguments many times as part of our #ThinkHand campaign.

Accept that we will need to use combination therapies to make a real difference to more late-stage MS. I am not necessarily talking about two anti-inflammatories, but an anti-inflammatory targeting adaptive immune responses in combination with a neuroprotective therapy. I agree there is a good argument for combining an anti-inflammatory that targets innate immune mechanisms, which targets hot microglia – with a classic anti-inflammatory against targeting adaptive immune mechanisms.

We need to ditch the EDSS. The whole community knows that the EDSS is not fit for purpose in more late-stage MS. We need to get the regulators to accept this. We also need to use outcome measures that capture the whole impact of MS on someone with MS. We are getting there with the new rendition of the MS functional composite. But in my opinion, this is not enough. We need more PROMS in the battery, in particular, ones that capture hand-and-arm function, cognition and quality of life. 

We need to think creatively about our trial design. I am not an expert here, but some in the community are pushing for adaptive trials, i.e. a multi-arm phase 2 trial with a seamless design allowing it to be converted into a phase 3 study. Pharma doesn’t necessarily like adaptive designs nor do the regulators. I do think we do need two phases to trials in more late-stage MS, i.e. the standard head-to-head phase with a robust primary outcome, say a multi-outcome composite, followed by an open-label extension where the study subjects remain blinded to their original treatment allocation. This will allow us to capture therapeutic lag. If we had done this we would have had licensed treatments for more late-stage MS decades ago. The logic behind this trial design is explained in detail in our length-dependent axonopathy paper (see below).

Acceptance of more sensitive biomarkers to get proof-of-concept trials done more quickly. I know I am biased, but I really think neurofilament level monitoring in the CSF and blood will provide us with this tool. This means we will be able to do phase 2 studies a lot quicker and more cheaply than we have done them in the past. 

Political changes are needed to incentivise the repurposing of off-patent drugs. We have discussed this on this blog endlessly and we even wrote a paper on the so called ‘Big Pharma Alternative’ to explain our thoughts on this.

Regulatory changes are also required. We need to get the FDA and EMA to accept wheelchair users in trials, newer outcome measures and combination therapy approach. 

More detailed cost-effective models that focus on loss of upper-limb function and bulbar function (swallowing and speech) are needed. It is clear from the health economic data that the costs associated with managing MS increase as disability advances. 

We also need to tackle ageing and its impact on worsening MS. I think the evidence that early, or premature, ageing as a result of reduced brain and cognitive reserve underpins worsening MS in older pwMS, is beyond doubt. What we need is some way of dissecting-out premature ageing from MS-specific mechanisms. Another issue with ageing is the emergence of comorbidities as a driver of worsening MS, in particular smoking, hypertension, hypercholesterolaemia, metabolic syndrome, diabetes and a sedentary lifestyle. I sit on many trial steering committees and we deal with this problem by simply putting an age cap on the trial population. This is the main reason why trials in late-stage MS usually have a ceiling of say 55, or 60, years of age. This is ageist and we must develop better tools for dealing with this issue.  

We need to manage expectations. PwMS are expecting an effective treatment to restore function or return them to normal. The latter is not going to happen. The best we can expect is to slow down the rate of worsening disability, or flat-line their disability, with anti-inflammatory and neuroprotective strategies. I say this knowing that in pathways with reserve capacity there is a possibility of improvement in function, but not enough improvement for us to falsely raise their hopes. To get substantial and meaningful improvements in disability we need new treatment strategies, possibly remyelination therapies that work, but we will almost certainly need treatments that promote axonal sprouting, synaptogenesis and plasticity mechanisms to restore function.

As you can see we are passionate about tackling more late-stage MS. We have thrown-out many babies (DMTs) with the bathwater. Why? We haven’t thought deeply enough about some of the issues highlighted in the points above. We need a serious debate about these issues and get on with the job of protecting cognition, arm, hand and bulbar function in people with more late-stage MS. The good news is that we now have licensed therapies for both primary and secondary progressive disease that can act as the platform on which to build our pyramid and to tackle MS holistically to improve longterm outcomes. 

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

CoI: multiple
Twitter: @gavinGiovannoni              Medium: @gavin_24211

#T4TD vascular comorbidities

Did you know if you have MS and vascular comorbidity you are likely to need a walking stick approximately 6 years earlier than if you did not have vascular comorbidity?  Importantly this 6-year difference in reaching EDSS 6.0 (requiring a walking stick) is larger than the treatment effect of a platform DMT.

As vascular comorbidities are largely preventable are you doing anything to prevent or optimally treat your own comorbidities? If not, you need to ask yourself why not? Self-management and taking responsibility for your own health is the order of the day; this has become the new normal. 

Vascular comorbidities = diabetes, hypertension, heart disease, hypercholesterolemia, peripheral vascular disease and smoking.

#T4TD = Thought for the Day

CoI: none for this post

Don’t mention the C-word

Don’t mention the C-word as it raises unnecessarily high expectations is what many of my colleagues say. I don’t agree with them. Showing we have cured, or not cured, MS is how we will ultimately test the hypothesis that MS is an autoimmune disease. 

People with MS (pwMS) want a cure. However, even if we have an MS cure in hand we may not prevent or reverse progressive disease.  Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or inflammation sets up processes that result in delayed worsening. The acute inflammatory MS lesion also damages axons and neurons but they manage to remain functioning albeit in a vulnerable state. However, this damage primes these axons and nerves to die off in the future. I like to call this delayed post-inflammatory neurodegeneration.

The mechanisms that result in delayed neurodegeneration of nerves or smouldering MS are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals (oxygen and nitrogen radicals), premature ageing, intrathecal plasma cell production of pathogenic autoantibodies, persistent viral infection, etc.

Clearly, anti-inflammatory drugs that prevent new lesion formation, such as natalizumab, alemtuzumab and ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that have damaged many nerve fibres, even if you go onto a highly effective DMT that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future. This is why did the PROXIMUS trial and are promoting the OXO trial; add-on neuroprotective drug to try and modify the primed but delayed die-off of neurons and axons in the future.

What protects you from entering the “clinically-apparent” secondary progressive phase of the disease is your reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I suspect that pwMS, who have been treated with highly-effective DMTs and who have now become secondary progressive, had a low reserve capacity and a large number of damaged nerve fibres that had been primed to die off. In other words, they were treated with DMTs too late to prevent SPMS in the vanguard pathway (the neuronal pathway with the most damage). This is why I keep pushing the message ‘early effective treatment’ is the only way to prevent secondary progressive MS. 

The same processes happen in PPMS the only difference is pwPPMS don’t have the earlier relapses that bring them to the attention of the medical profession in the initial stages of the disease. 

There are two conclusions to be drawn from these observations; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, and (2) we need additional add-on neuroprotective, remyelinating and neurorestorative therapies to target the delayed neurodegenerative processes referred to above. 

In addition to this, we need to avoid and/or reverse any other factors that prematurely age the nervous system. The ageing hypothesis of progressive MS is a major factor that underpins our Brain Health campaign, which targets non-specific factors that have been associated with more rapid progression in MS (smoking, co-morbidities, lack of exercise, infections, etc.). Common to all these factors is that they reduce your reserve and hence bring forward and speed up progressive MS.

So unless you are rendered NEDA early in the course of your disease it may not prevent you from entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, our licensed DMTs don’t kill long-lived plasma cells that continue to make intrathecal (within the CNS) antibodies that may drive progressive MS. The exceptions may be natalizumab and cladribine. 

There are several reports of pwMS on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a ‘niche’ or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard.

A recent report from Poland showed that about 50% of pwMS treated with intravenous cladribine more than 10-years ago had lost their oligoclonal IgG bands and were more likely to be stable than the those who have not lost their OCBs. There is old and new data emerging suggesting that the immunoglobulin is present in the cerebrospinal fluid of pwMS is toxic to oligodendrocytes (cells that make myelin) and can stimulate microglia. Just maybe the immunoglobulins are responsible for the slowly expanding lesions (SELs) or the subpial grey matter lesions that are such an important part of progressive MS

To target plasma cells, which are long-lived, we will need add-on therapies. This is high on our list of priorities and we are starting the SIZOMUS trial, COVID-19 permitting, to test a therapy for myeloma (malignant plasma cells) in MS. We are also looking at the effects of cladribine in a similar way (CLADRI–PLUS and CLAD-B studies) and we also want to look at the impact of very early treatment of MS with natalizumab as well (ATTACK-MS study). We also have a longish list of other potential therapies we would like to try as well, but we need help with this, i.e. funding, colleagues to share the workload and potential Pharma interest to give us access to some of the compounds we have identified as potentially promising. 

Our challenge and objective are to scrub the MS brain free of B-cells and plasma cells!

Some people don’t buy into this hypothesis, but it is also supported by the observation that pwMS who receive higher doses of ocrelizumab do better than those receiving lower doses. I think that this may be related to more CNS penetration of ocrelizumab and is why I have proposed that Roche do a double-dose or DODO study. In relation to the DODO study, it is not necessarily about giving double-dose ocrelizumab indefinitely, but only early on as induction therapy and then to explore post-induction safer maintenance therapies (BTKi or teriflunomide). Please see the iTeri and iBruT studies in the slide show below. I can’t stress how important these observations are and they have made me question whether or not we have optimised the dose of both ocrelizumab and rituximab and other emerging anti-CD20 therapies. 

 

So yes, we may be able to cure you of MS with IRTs but you may not realise it depending on when in your course you are treated. So as you can see we as an MS community have a lot still to do when it comes to improving disease outcomes of people with MS and yes we need to mention the C-word. We need to define what a cure means and how to look for it so that we can declare victory or not. 

CoI: multiple

PS there is quite a lot chatter going on Twitter in relation to this post.

https://platform.twitter.com/widgets.js

MAKING ONCOLOGISING MS A REALITY

Barts-MS rose-tinted-odometer  N/A

Yesterday’s PMSA meeting was very interesting. It is clear the field of MS is at a cross-roads and that Pharma needs the wider MS community to help them change the game. If we don’t I suspect we won’t see the next generation of treatments being developed to target the ‘real MS’ or ‘smouldering disease’.

It was clear that combination therapies are needed, but how we make them happen is another story. Regulators need to understand that we need to go beyond inflammation and treat MS as one disease. I tried to convey this message in my presentation. What I am staying is the real MS is essentially primary progressive MS or smouldering MS. Our anti-inflammatory therapies convert relapsing forms of MS into primary progressive MS and we, therefore, need to combine these groups, i.e. those who are NEDA-2 and getting worse into one group for add-on trials.

My proposal to oncologise MS and create a trials platform was presented by both Jeremy Chataway and Ludwig Kappos. It is reassuring that these two giants of the MS world are supportive of the idea. I have therefore designed the skeleton of an O’ADD-ON and DADD platform for discussion. In reality, these platforms should have been set-up yesterday.

Doing registry-type trials is now the norm in most fields of oncology. I, therefore, see no reason why we can’t steal their ideas and apply them to MS. The question which fish will bite first; Roche or Biogen? There is nothing like a bit of competition and the fear of missing out (FOMO) to get people to act.

What do you think of these platforms? I am very interested to hear if you think this is feasible or not? An ocrelizumab and/or DMF platform will at least create the base for Roche and Biogen to develop their own add-on compounds but will allow them to partner with other Pharma companies, for example, Abbvie and elezanumab, and with academia. Although these platforms will be expensive I am sure the investment will pay massive dividends down the line for pwMS, society and industry.

CoI: multiple

P.S. In response to some of the comments below. The following infographic is a crude attempt to explain what I mean when I say that current DMTs convert RRMS into PPMS or smouldering MS. PwPPMS simply have a much longer asymptomatic and prodromal phase so that when they present with symptoms and get diagnosed they have lost more brain and spinal cord. In other words, pwPPMS have more advanced MS and have less reserve compared to people with early relapse-onset MS. The latter explains why the treatment response is less in both SPMS and PPMS.

Progressive MS is a misnomer

Barts-MS rose-tinted-odometer – zero stars

I am in Milan at the International Progressive MS Alliance Industry Forum Meeting. The aims of the meeting are to:

  1. Discuss challenges understanding and measuring progression and its impact on drug labels
  2. Discuss regulatory issues, opportunities and implications for drug labels and regulatory approvals
  3. Discuss links and opportunities for industry and the Alliance to contribute feedback to the International Advisory Committee on Clinical Trials in Multiple Sclerosis activities on phenotype classification and clinical trials
  4. Share lessons from recent clinical trials/development programs and how they impact the challenges of developing drugs for progression in MS

I have been asked to speak on the implications of disease classification for drug development, regulatory approval and drug labelling. This topic is fine, but it is far removed from people with the disease, which is why I am going to base my talk on case scenarios to illustrate how absurd the current status quo is for pwMS and the wider MS community.

As a pre-read to these case scenarios, I suggest you read a previous post of mine about progressive MS.

Case scenario 1

48-yr old woman
MS x 22 year
Last relapse 8 years ago – lower limb weakness and exacerbation of bladder problems

Annual MRI scans:
Last scan 3  years ago
Marked brain and spinal cord atrophy

Poor gait, now needs to use walking sticks outdoors and can manage only 10-20m; uses scooter outdoors
Bladder and bowel problems  with recurrent UTIs
Significant cognitive impairment

EDSS = 6.5

DMTs: Interferon-beta-1a stopped 3 years

Does this patient have active SPMS?
Does she have active SPMS?

Case scenario 2a

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago / MRI stable

EDSS = 3.0 (stable)

Difficulty running and walking long distance; Fitbit data over the last 3 years showing objective reduction in daily activity

Does this patient have SPMS?
Is the patient eligible for a DMT switch?
Is the patient eligible siponimod?

Case scenario 2b

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago / MRI stable

EDSS = 3.0 (stable)

Difficulty running and walking long distance; Fitbit data over the last 3 years showing objective reduction in daily activity

Labeled as having inactive SPMS
Under NHSE guidelines fingolimod is stopped and 10 weeks later he presents with new onset paraplegia
MRI shows longitudinally extensive myelitis and >30 new Gd-enhancing lesions over the neuraxis

Does this patient have SPMS?
Is the patient eligible siponimod?
What happens if his treatment response is suboptimal on spinoimod?

Case scenario 2c

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago / MRI stable except progressive brain volume loss (0.78% per year over the last 3 years; Icometrix)

EDSS = 3.0 (stable)

Does this patient have SPMS?
Is the patient eligible for a DMT switch?
Is the patient eligible siponimod?

Case scenario 2d

36-yr old male
MS x 12 years
Previously treated with Rebif-44 x 6 years; failed due to ongoing relapses
Switched to fingolimod 3 years ago
Last relapse 4 years ago

EDSS = 3.0 (stable), but has noticed increasing forgetfulness at work and difficulty using a new software system
T25W & 9HPT stable
SDMT worsening:
2017 = 48 
2018 = 45 
2018 = 41
2019 = 39

Does this patient have SPMS?
Is the patient eligible for a DMT switch?
Is the patient eligible siponimod?

If you work through the logic of each of these case scenarios that are based on real-life examples you will quickly see that the current status quo is not compatible with the biology of the disease and makes very little sense; in other words, classifying MS as three diseases is absurd.

CoI: multiple

Do you want a cure?

MSers want a cure. However, even if we have an MS cure in hand we may not prevent or reverse progressive disease. How can this be?

Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or it can damage nerves and leave them functioning, but the resulting damage primes them to die off in the future; I call this delayed neurodegeneration.

The mechanisms that result in delayed neurodegeneration of nerves or smouldering MS are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals (oxygen and nitrogen radicals), premature ageing, intrathecal plasma cell production of pathogenic autoantibodies, etc.

Clearly, anti-inflammatory drugs that prevent new lesions formation, such as natalizumab, alemtuzumab and ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that have damaged many nerve fibres, even if you go onto a highly effective DMT that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future. This is why did the PROXIMUS trial and are promoting the OXO trial; add-on neuroprotective drug to try and modify the delayed die-off of neurons and axons.

What protects you from entering the clinically-apparent secondary progressive phase of the disease is reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I suspect that MSers, who have been treated with highly-effective DMTs and have now become secondary progressive, had a low reserve capacity and a large number of damaged nerve fibres that had been primed to die off in the future. In other words, they were treated with DMTs too late to prevent SPMS. This is why we keep pushing the message ‘early effective treatment’ is the only way to prevent secondary progressive MS.

There are two conclusions to be drawn from these observations; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, and (2) we need additional add-on neuroprotective therapies to target the delayed neurodegenerative processes referred to above. The latter includes avoiding or reversing factors that prematurely age the nervous system.

The ageing hypothesis of progressive MS is a major factor that underpins our Brain Health campaign, which targets non-specific factors that have been associated with more rapid progression in MS (smoking, co-morbidities, lack of exercise, infections, etc.).  

So unless you are rendered NEDA early in the course of your disease it may not prevent you from entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, our licensed DMTs don’t kill long-lived plasma cells that continue to make intrathecal (within the CNS) antibodies that my drive progressive MS. The exception may be natalizumab. There are several reports of MSers on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a ‘niche’ or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard.

To target plasma cells, which are long-lived, we will need add-on therapies. This is high on our list of priorities and we are starting the SIZOMUS trial to test a therapy for myeloma (malignant plasma cells) in MS. Can we scrub the MS brain free of plasma cells?

CoI: multiple

Inactive MS; does it exist?

I had an interesting discussion with some like-minded colleagues recently about active and inactive MS. We seemed to agree on what active MS is, be it in the relapsing or progressive phases of MS. However, we couldn’t really agree on what inactive MS is. Take this following case scenario; many said he was inactive, but others felt he had active MS and should have his treatment switched. Would you agree?

When you look at post-mortem studies of people dying with endstage MS they all have active inflammation within their brains. Active inflammation refers to both adaptive (memory responses) and innate (hard-wired) immune responses. MSers at death still have T-cells, B-cells and plasma cells in their brains in addition to astrocyte and microglial activation. 

If we extrapolate these pathological findings to life then all MSers have active MS. What is the solution in terms of forming a common nomenclature? Surely MS is a biological disease rather than a clinical disease? If this is the case we need to come up with a biological classification system to describe active and inactive MS.  

On reflection, I think we need to get rid of the terms active and inactive and describe what we mean pathologically using metrics. For example, 

  1. This patient has evidence of ongoing focal inflammation (relapses, new and/or enlarging T2 lesions and/or Gd-enhancing lesions and/or raised CSF NFL levels) in the last 12 or 24 months. 
  2. This patient has no evidence of ongoing focal inflammation in the last 24 months but has worsening disability (physical and/or cognitive) and evidence of smouldering MS with increased brain/spinal cord atrophy and/or an increasing T1 black volume. 
  3. This patient has no evidence of ongoing focal inflammation in the last 24 months, is stable clinically (physical and cognitive) and has no evidence of smouldering MS, i.e. no increased brain/spinal cord atrophy and a stable T1 black volume. 

I suspect that we will have very few MSers in category 3, simply because with an MS-centric view of the world we are forgetting that MSers are human and will age and will get comorbidities. Therefore, how do we include ageing and comorbidities, which affect these biomarkers, into this classification system? In addition, none of our metrics is black-and-white so there is scope for miss-classification. What is clear that if you take this approach then MS is one, and not two or three, diseases. A person with PPMS with new lesions will be treated in the same way as someone in the relapsing-remitting phase of the disease. Do you have a problem with this?

Thoughts, please?  

CoI: multiple

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.

What’s your excuse?

What will it take to get me to stop smoking?

If you are a smoker and continue to smoke you need to think about how you want to manage your own MS. We debate endlessly about the lack of progress in developing effective treatments to slow down the worsening of MS and ignore the obvious. The first study below implies that by simply stopping smoking it will have a major impact on the outcome of your MS. Do you want to stop smoking? If you do please ask your GP or family doctor to refer you to a stop smoking cessation clinic; please note it is very difficult to stop smoking without professional help.

I am going to use this post to blow our own trumpet. In this week’s New England Journal of Medicine is a paper from a group in our University showing that e-cigarettes are superior to nicotine replacement therapies in getting people to stop smoking. This is good news; e-cigarettes give those who are really addicted to nicotine the necessary ‘nicotine hit’, whilst reducing the harm associated with cigarettes. In my opinion, there is now really now no excuse for someone with MS to continue smoking. Or am I wrong?

How smoking speeds up the onset and rate of progressive MS is unknown. Smoking may simply unregulate proinflammatory mechanisms, reduce recovery mechanisms in the brain and spinal cord or speed up the development of comorbidities in particular vascular disease, which in turn speeds up the rate of worsening in progressive MS.

The effect of smoking on progressive MS may be independent of it being a risk factor for developing MS in the first place. We need more research in this area to see what it is about smoking that triggers MS. Based on other Swedish data it appears that it is something that is in smoked tobacco that is to blame. In Sweden use of snuff or non-smoked tobacco, does not increase your risk of getting MS; in fact, the risk of getting MS in snuff users is actually lower than that of the general population.

With my #PreventMS hat on is that if we get the population not to start smoking in the first place we can prevent 1 in 5 future people from developing MS. This is why it upsets me so much when my own children smoke. Even more worrying is that if you are loaded with the correct genetic factors that predispose you to develop MS your odds of getting MS are increased dramatically if you smoke. The latter is more reason to make sure your brothers and sisters, children, nephews and nieces don’t smoke. Tragically this is easier said than done.

Study 1

Ramanujam et al. Effect of Smoking Cessation on Multiple Sclerosis Prognosis. JAMA Neurol. 2015 Oct 1;72(10):1117-1123.

IMPORTANCE: Smoking tobacco is a well-established risk factor for multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system usually characterized by bouts and remissions and typically followed by a secondary progressive (SP) course. However, it is not clear whether smoking after diagnosis is detrimental.

OBJECTIVE: To determine whether smoking after MS diagnosis is associated with a change in time to SP disease.

DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of patients with prevalent MS who smoked at diagnosis (n = 728) taken from the Genes and Environment in Multiple Sclerosis Study, which consists of patients from the Swedish National MS Registry. The study entrance date was at time of first-year smoking. The study was conducted between November 2008 and December 2011, with patient environmental data collected from November 2009 to March 2011 via questionnaire. Study participants were from all counties in Sweden diagnosed as having MS at the time of the Genes and Environment in Multiple Sclerosis Study and registered in the Swedish National MS Registry. Patients with MS with relapsing-remitting disease course or SP were included. These patients’ conditions were diagnosed according to the McDonald criteria and the patients responded to recruitment letters with detailed questionnaires.

EXPOSURE: Smoking, considered yearly after diagnosis and combined into a time-invariant covariate before diagnosis.

MAIN OUTCOMES AND MEASURES: Time to SPMS, measured using an accelerated failure time model, with smoking as a time-varying covariate. Other covariates included sex, age at diagnosis, snuff use, and smoking before diagnosis.

RESULTS: The optimized model illustrated that each additional year of smoking after diagnosis accelerated the time to conversion to SPMS by 4.7% (acceleration factor, 1.047; 95% CI, 1.023-1.072; P < .001). Kaplan-Meier plots demonstrated that those who continued to smoke continuously each year after diagnosis converted to SPMS faster than those who quit smoking, reaching SP disease at 48 and 56 years of age, respectively.

CONCLUSIONS AND RELEVANCE: This study provides evidence that continued smoking is associated with an acceleration in time to SPMS and that those who quit fare better. Therefore, we propose that patients with MS should be advised to stop smoking once a diagnosis has been made, not only to lessen risks for comorbidities, but also to avoid aggravating MS-related disability.

Study 2

Hajeck et al. A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy. N Engl J Med. 2019 Jan 30.

BACKGROUND:  E-cigarettes are commonly used in attempts to stop smoking, but evidence is limited regarding their effectiveness as compared with that of nicotine products approved as smoking-cessation treatments.

METHODS: We randomly assigned adults attending U.K. National Health Service stop-smoking services to either nicotine-replacement products of their choice, including product combinations, provided for up to 3 months, or an e-cigarette starter pack (a second-generation refillable e-cigarette with one bottle of nicotine e-liquid [18 mg per milliliter]), with a recommendation to purchase further e-liquids of the flavor and strength of their choice. Treatment included weekly behavioral support for at least 4 weeks. The primary outcome was sustained abstinence for 1 year, which was validated biochemically at the final visit. Participants who were lost to follow-up or did not provide biochemical validation were considered to not be abstinent. Secondary outcomes included participant-reported treatment usage and respiratory symptoms.

RESULTS: A total of 886 participants underwent randomization. The 1-year abstinence rate was 18.0% in the e-cigarette group, as compared with 9.9% in the nicotine-replacement group (relative risk, 1.83; 95% confidence interval [CI], 1.30 to 2.58; P<0.001). Among participants with 1-year abstinence, those in the e-cigarette group were more likely than those in the nicotine-replacement group to use their assigned product at 52 weeks (80% [63 of 79 participants] vs. 9% [4 of 44 participants]). Overall, throat or mouth irritation was reported more frequently in the e-cigarette group (65.3%, vs. 51.2% in the nicotine-replacement group) and nausea more frequently in the nicotine-replacement group (37.9%, vs. 31.3% in the e-cigarette group). The e-cigarette group reported greater declines in the incidence of cough and phlegm production from baseline to 52 weeks than did the nicotine-replacement group (relative risk for cough, 0.8; 95% CI, 0.6 to 0.9; relative risk for phlegm, 0.7; 95% CI, 0.6 to 0.9). There were no significant between-group differences in the incidence of wheezing or shortness of breath.

CONCLUSIONS: E-cigarettes were more effective for smoking cessation than nicotine-replacement therapy, when both products were accompanied by behavioral support. (Funded by the National Institute for Health Research and Cancer Research UK; Current Controlled Trials number, ISRCTN60477608 .).

Study 3

Hedström et al. Smoking is a major preventable risk factor for multiple sclerosis.Mult Scler. 2015 Oct 12. pii: 1352458515609794.

BACKGROUND: Both smoking and exposure to passive smoking have repeatedly been associated with increased multiple sclerosis (MS) risk, but have never before been studied together. We assessed the public health impact of these factors.

METHODS: In a Swedish population-based case-control study (2455 cases, 5336 controls), we calculated odds ratios of developing MS associated with different categories of tobacco smoke exposure, together with 95% confidence intervals, by using logistic regression. The excess proportion of cases attributable to smoking and passive smoking was calculated as a percentage.

RESULTS: Both smoking and exposure to passive smoking contribute to MS risk in a dose-dependent manner. At the population level, 20.4% of all cases were attributable to smoke exposure. Among subjects carrying the genetic risk factor HLA-DRB1*15 but lacking HLA-A*02, 41% of the MS cases were attributable to smoking.

CONCLUSIONS: From a public health perspective, the impact of smoking and passive smoking on MS risk is considerable. Preventive measures in order to reduce tobacco smoke exposure are, therefore, essential. In particular, individuals with a history of MS in the family should be informed regarding the impact of smoking on the risk of MS, and the importance of preventing their children from being exposed to passive smoke.