How soon will MSers have brain volume measurements as part of their annual assessments?
As a reader of this blog, you may be aware that ‘life is a sexually-transmitted age-dependent terminal neurodegenerative disease’. Homo sapiens, as a species, is pushing its biological capabilities to its limits. We have conquered most diseases that used to cull us before our mid-thirties and the end of our reproductive age. In the same way, as the technology sector has learnt to build in senescence into its products to ensure we upgrade our gadgets every 18-24 months, evolution has selected for biological senescence to make sure the current generation does not freeload on the next generation. When we have finite resources, why should we waste precious food on the older generation when we have to ensure the current generation reproduces to pass on its genes? A counter-argument to this ruthless biological perspective is that cultural evolution now takes precedence over biological evolution and it is societies and not individuals who are driving evolution. Culture and some heritable traits have clearly interacted with our environments, which explains why some isolated populations are enriched for people who are healthy agers. We are learning from studying these populations and unpacking the relevant biology to identify future treatment targets for healthy ageing. Do you want to be a healthy or super ager? If you have MS this is unlikely to happen.
These insights are telling us ageing is a biological process and therefore hackable, i.e. we will at some point learn how to reprogramme ourselves to reverse or at a minimum delay the effects of ageing. The reason I say this that we already do this in the form of reproduction; we produce sperm and eggs that go onto to recombine and form offspring that have their senescence programmes set to zero. Why can’t we do this at any stage of life?
Cellular senescence is accelerated by various stressors, which at the level of the whole organism results in premature ageing. The corollary of this is that certain lifestyle interventions appear to delay ageing mechanisms, or at least increases the resilience of the organism so that the consequences of ageing only become apparent much later on in life. Our increasing ability to manipulate these stressors and/or resilience mechanisms should empower individuals to maximise their health and wellness for future gain.
Is this relevant for MS? Yes, it must be. Firstly, many of the cellular stressors that result in ageing are upregulated in the brains of MSers. We also know that one of the resilience mechanisms that protects us from age-related cognitive impairment is brain and cognitive reserve. As MSers get old you rely on these exact same mechanism to allow yourselves to age healthily. If you get to old age with a deficit how can you expect to age normally? As MS starts to shred your brain reserve from the earliest stages of the disease the treatment objective should be to address this from the outset? Therefore, how do we get the MS community to shift its treatment target beyond NEDA and to focus on the end-organ and the preservation of brain reserve?
One possible option would be to equip MS healthcare professionals (HCPs) and you the MSers with the tools to monitor end-organ damage more closely. Wouldn’t you want to know what is happening to your brain volume on an annual basis? Would you want to know if you are losing more brain than average?
Several companies are beginning to scale up their image analysis software and providing it online for MS centres and possibly individuals to measure their own brain volume and to get feedback based on a normogram; i.e. a normal distribution of brain volumes for age and to plot where on the standard curve you are. Your brain volume can then be measured and plotted annually to establish your trajectory.
The naysayers will say that this technology can’t be used on an individual basis as it has not been validated in clinical practice. The naysayers are in for a big surprise; I suspect the regulators are will approve these algorithms long before they are ready to incorporate them into routine clinical care. However, these very same naysayers often present group data at meetings with great confidence. Group data is what it is, an academic construct, that is far removed from clinical care and the individual with MS. My personal opinion about biomarkers is that you need to put them out there, with obvious disclaimers, and see how they are used. Technology itself works magic in many different ways.
I think having personal annual brain atrophy data will get both the neurologists, other HCPs and MSers to think differently about managing MS and it may be the nudge we need to treat MS more effectively early on and to change our treatment target. I also have little doubt that the methodology of measuring whole brain volume, grey and white matter volumes, lesion volume and the number and volume of lesions expanding will only get better and more accurate with time. So bring it on!
Do you agree with me? If not, let’s have a debate. End-organ damage and brain volume is very topical at the moment.
Do we have the right cell target in MS? Yes and no; we need a multicellular approach.
Recently the attention in MS has been on the B-cell as if it was the holy grail of MS treatments. It is not.
In several posts, over the last few weeks, I have made the case that the B-cell is important, probably as an antigen presenting cell, but it is not the ‘be all and end all’ of MS treatments. It is clear that rebound post-natalizumab is driven my B-cells and the positive data on the first BTK inhibitor would indicate that the B-cells are working via the B-cell receptor on antigen presentation. If only we knew what these antigens were we would have a much better handle on the cause of MS.
I know this science stuff is hard, but it is important. At the end of the day, the nut and bolts of MS must be molecular; molecules mean treatment targets and potentially more focused and hopefully better and safer treatments in the future.
I have stressed that simply targeting B-cells in both the periphery and central nervous system will not be enough to effectively treat MS in the long-term. When we look at end-organ damage markers in pwMS who are on B-cell therapies they have ongoing brain volume loss, albeit at a lower rate, and enlarging lesions (T1 black holes), which are both indicative of ongoing smouldering MS. So what do we need to do? I have provided circumstantial evidence that NIRTs (non-selective immune reconstitution therapies) have a slight edge on the B-cell therapies and this may be because they are also targeting T-cells. The latter, however, comes at a price of greater adverse events in relation to immunosuppression. The proportion of MSers on NIRTs who experience disability improvement seems higher when compared to the anti-B cell agents, which indicates that NIRTs are doing something else over and above their effect on the B-cell compartment. However, based on their overall safety profile it is unlikely that the NIRTs (alemtuzumab & HSCT) will be a therapeutic strategy that the wider MS community will adopt with vigour. Although from comments on this blog there is an informed group of MSers who feel hard done by because their HCPs won’t offer them the option of using NIRTs first-line, i.e. very early in the course of their disease when they have the most to gain from these therapies.
Is there anything else we can do to improve on the profile of B-cell therapies to make them better? Yes, I think there is. Targeting the plasma cell,in addition to the B-cell. Data on plasma cells goes back decades and surprisingly the plasma cell has never been a major therapeutic target in MS. John Prineas, one of my MS heroes, has always stressed the importance of the plasma cell in MS. His paper below from 1978 documents just how enriched the brains of MSers are with this population of cells. What is often not stressed is that the biology of plasma cells is so so different to the B-cell, which opens up new therapeutic targets that are quite different to those in the T and B cell compartments. More on this topic another time.
You are aware of the recent publication showing that about 55% of Polish MSers treated with intravenous cladribine lost their oligoclonal bands 10 or more years after treatment and if they did lose their OCBs they tended to have lower EDSS scores. We have known for years that MSers, with either relapse-onset or primary progressive diseases, who don’t have OCBs do better. There is also evidence from biomarker and pathology studies that the OCBs may be driving several of the disease processes that have been linked to advanced or progressive MS, i.e. microglial activation and grey matter pathology. Based on these observations, we hypothesise that OCBs are very likely to be pathogenic in MS, which is why we are embarking a research programme to try and target the plasma cells within the CNS of MSers. Do you think we are crazy?
To get a handle on the plasma cell we are going to have to study what happens in the spinal fluid. There are simply too many plasma cells in the periphery which will drown out any signal from the CNS. To participate in the studies we are planning we will have to perform serial, annual, lumbar punctures or spinal taps to see if our add-on therapy is killing and/or reducing the number of plasma cells in your brain and spinal cords. The good news is that we have de-risked the lumbar puncture with the use of atraumatic needles and screening. I never thought I would be saying this but most of our patients don’t mind having LPs, particularly when they understand the reason behind the LP. CSF neurofilament levels are now part of our prognostic profile of MSers at baseline and we are increasingly using them to assess response, or lack of response, to treatment. So if you want to be treated and treated-2-target beyond NEDA, and beyond the B-cell, then having an LP is important.
We hope our proposed plasma cells studies will lead to a mindset that goes beyond the B-cell to target some of the mechanisms that are responsible for smouldering MS.
Perivascular cells in CNS tissue from six multiple sclerosis (MS) patients and a patient with motor neuron disease were examined by light and electron microscopy. Lymph node tissue from one MS patient was also examined. CNS perivascular macrophages in both MA and motor neuron disease were found to closely resemble free macrophages elsewhere in the body except that they often contained unusually large primary lysosomes. Cytoplasmic inclusions consisting of membrane-bound stacks of curved linear profiles, presumed to be a product of myelin degradation, were constantly observed in microglia in MS plaques but were rarely observed in perivascular macrophages in the same area. Unidentified cylindrical bodies were observed within cysternae of rough endoplasmic reticulum in some lymph node cells. Quantitative studies of the perivascular cell population in one MS case revealed, in histologically normal white matter 260 lymphocytes and 178 plasma cells per cubic millimeter of fresh tissue. Typical chronic plaque tissue without obvious inflammatory cell cuffing contained 1772 plasma cells per cubic millimeter of fresh tissue. No plasma cells were observed in the CNS in motor neuron disease. The results of this study suggest that perivascular macrophages in the CNS represent a specialized population of monocyte-derived free macrophages, that these cells differ functionally from microglial cells, and that the digestion of myelin breakdown products in MS requires the participation of both cell types. The results also suggest that in some chronic MS cases there is a large, permanent population of CNS plasma cells that persists, like the elevated cerebrospinal fluid IgG level in this disease, for the life of the patient, that these cells, rather than inflammatory cells in fresh lesions, are the major source of this raised IgG, and that the existence of such a population of cells may indicate the continuing expression of antigens in chronic MS lesions in the absence of fresh lesion formation.
In response to a comment from one of our readers, I am starting a series of posts called #MS-Selfie, which is derived from the term self-management. These posts are a long read but will help you manage your own MS.
Over the last few weeks, many of my posts have focused on MS-specific mechanisms underlying why pwMS become disabled and how DMTs can delay, or prevent, this damage from occurring. The message as always is to treat early and effectively, and if you want the best chance of doing well over your lifetime you need to consider flipping the pyramid and going for high-efficacy DMTs. I have also highlighted subtle, but potentially important differences, between the non-selective immune reconstitution therapies (NIRTs) and the more selective immune reconstitution therapies (SIRTs) and maintenance therapies in terms of their impact on end-organ damage markers and disability improvement. These two will almost certainly become more important as a treatment target in the next decade.
You may or may not know about Sir Dave Brailsford and his philosophy of marginal gains. Sir Dave applied a theory of marginal gains to cycling; he proposed that if the British team broke down everything they could think of that goes into competing on a bike, and then improved each element by 1%, they would achieve a significant aggregated increase in performance. He got the British Cycling to adopt this and the rest is history. Britain dominates the World Championships, Olympic Games, Paralympics and now the Tour de France with Team Sky. So what this got to do with MS?
If we approached the management of MS in the same way, we will almost certainly improve the outcome of British people living with MS. To optimise your outcome it is not good enough just to focus on MS DMTs, but all the factors that could worsen or improve your MS.
This is post is about one of these factors infections and bladder dysfunction.
Relapses and infections
Infections, in particular, viral infections, are a known trigger of relapse. You are more than twice as likely to have a relapse in the week prior to, or the 5 weeks after, an infection. In the study below infections in this paper were mainly symptomatic upper respiratory infections due to viruses, so the risk may be much higher if we could also count hidden or asymptomatic infections.
What do I mean by asymptomatic infections? We are continuously being exposed to new viruses that infect us but don’t necessarily cause symptoms. An example of this is the JC virus that causes PML (progressive multifocal leukoencephalopathy). When we initially become infected with the JC virus it does not cause any symptoms; it simply gets into our body and persists. It persists as an asymptomatic lytic infection. In the majority of us, persistent JC virus infection doesn’t cause any problems. Only if we become immunocompromised do we have a chance of this virus mutating and causing PML. Similarly, for the majority of us when we get infected with Epstein-Barr virus (EBV) it does not cause symptoms; only the minority of us get glandular fever or infectious mononucleosis. The same applies to another herpes virus called CMV or cytomegalovirus; asymptomatic infection is the rule. What is interesting about the herpes viruses is that they become latent in the body and reactivate every now and then. These reactivations of latent viruses are usually asymptomatic but are strong enough to stimulate the immune system and may trigger relapses. In fact, there is some evidence that this may actually be the case.
When I did my PhD I studied a marker of immune activation on a daily basis in pwMS over many months. I found that immune activation usually preceded the occurrence of new MRI lesions by a few weeks. Please remember new MRI lesions are the equivalent of subclinical relapses. I, therefore, proposed in my thesis that latent viral reactivations may be the factor responsible for this immune activation, which then triggers MS disease activity. This is one of the reasons why I am so interested in the viral MS hypothesis. Virus-induced MS exacerbations don’t have to apply to exogenous viruses only, i.e. viruses that come from outside the body but could also apply to endogenous viruses, i.e. viruses that reside in our bodies or genome. The latter refers to human endogenous retroviruses (HERVs). This is one of the hypotheses that underpins our Charcot Project. Can we treat MS by reducing endogenous viral reactivation (HERVs)? Can we treat MS by preventing reactivation of latent herpes viruses, in particular, EBV? This is why we are exploring add-on antiviral studies to see if we can prevent MS disease reactivation.
It is very difficult to avoid viral infections. The one thing you can do is have your annual flu vaccine and try to avoid coming into contact with people who are clearly ill and potentially shedding virus.
Please, note that the observation of infections triggering relapses is not limited to viral infections, but also applies to bacterial infections, in particular, urinary tract infections. This is why we have to improve the management of bladder problems in pwMS with the aim of preventing or reducing urinary tract infections (UTIs). PwMS with recurrent UTIs do worse than pwMS without UTIs. However, to prevent or reduce the frequency of UTIs you have to know how MS causes bladder problems and to deal with them.
Bladder dysfunction
Bladder dysfunction is the most common symptomatic problem I have to deal with in the clinic. More than 50% of pwMS have bladder problems. Bladder dysfunction in pwMS is one of the integrators of early damage, particularly spinal cord damage, and an early read-out of a poor prognosis. I, therefore, take symptoms of bladder problems seriously as it has implications around MS prognosis and its treatment. For example, if you have early bladder symptoms may choose a more effective therapy early on rather than take chance on a lower efficacy DMT waiting to see if you are a responder or not.
Why do pwMS who develop bladder dysfunction do worse than those who don’t have bladder symptoms? The bladder is a complicated organ with several neurological components that can be affected by MS and hence is sensitive to damage. The descending nerve fibres that travel from the brain to the lower spinal segments are very long and hence have a greater chance of being affected by MS lesions in their path to the bladder centre in the lower spinal cord. The same is true for motor fibres that control movement in the lower legs. The bladder, unlike the motor fibres to the leg, is more complicated because of the need to coordinate the different muscles. Therefore any progressive MS damage is more likely to manifest with bladder dysfunction early on. This is why I now include bladder problems in my list of poor prognostic factors in MS.
The bladder has two muscles that need to be coordinated in their action for the bladder to function normally. The detrusor or balloon muscle and the sphincter or valve muscles When the bladder is filling up the detrusor muscle has to relax to allow the bladder to expand with urine and the sphincter has to contract to keep the urine in the bladder. The opposite occurs when you pass urine; the sphincter or valve opens and the detrusor contracts to empty the bladder.
Hesitancy
What happens if the two muscles are not coordinated? This causes the symptom of hesitancy, i.e. when you try and pass urine the sphincter won’t open and you have to wait for the bladder to open; pwMS find this very frustrating. The sphincter can also close as you passing urine, which breaks up the urine stream or prevents you from emptying your bladder completely. The latter also causes dribbling. The medical term for incoordination of the bladder muscles is dyssynergia or more correctly detrusor-sphincter-dyssynergia (DSD). The drug treatment for DSD includes the so-called alpha-blockers ( prazosin, indoramin, tamsulosin, alfuzosin, doxazosin and terazosin). Other strategies include small bladder stimulators or vibrators; these are placed over the pubic area and work by blocking signals that inhibit the sphincters. The vibrators work in some pwMS and may help relax the sphincter. It is also important to try and relax when passing urine; this often helps improve hesitancy. The sound of running water, for example from a tap, may trigger the relaxation of the sphincter. This can be a problem in public toilets when opening a nearby tap may not be possible or inappropriate. Some pwMS find pressing on the lower abdomen helps. If all else fails regarding hesitancy intermittent self-catheterisation (ISC) may be the only option.
Frequency
In MS the commonest bladder problem is spasticity, or irritability, of the detrusor muscle. The detrusor can’t relax and this prevents the bladder filling to its maximum capacity. Frequent spasms of the detrusor muscle tell the brain that it is full and you need to go to the toilet. This causes frequency; i.e. the need to go to the toilet many times during the day and night. Frequency often goes with the symptom of urgency, the need to get to the toilet as quickly as possible to prevent yourself from being incontinent. Incontinence occurs as you often lose the ability to suppress or ignore the signals from the detrusor muscle and the sphincter relaxes or opens as part of spinal cord reflex. We typically treat this problem with the so-called anti-cholinergic drugs, for example, oxybutynin, solifenacin or tolterodine. The older generation anticholinergics such as oxybutynin cross the blood-brain-barrier and enter the brain where they can exacerbate cognitive problems in pwMS. This is why I avoid using them. The commonest side-effect of anticholinergics is dryness of the mouth and they can make constipation worse. There is also a risk that they will relax the bladder too much and precipitate urinary retention. All pwMS must be warned about this problem when starting anticholinergics; I have several pwMS under my care go into retention on starting anticholinergics.
The good news is that we now have a new muscle relaxant mirabegron (Betmiga), which works by activating the β3 adrenergic receptor in the detrusor muscle. I increasingly using it to avoid the side effects associated with the anticholinergics.
Urgency
When urgency is a problem try some distraction techniques such as breathing exercises and mental tricks (for example, counting) to take your mind off the bladder may be helpful. If urinary frequency is your main problem you may want to try and retrain your bladder by holding on for as long as you can each time before passing urine. The aim is to train the detrusor muscle to expand more so that it can hold on for longer when you need to go to the toilet. In my experience these behavioural techniques rarely work for long; MS is a relapsing and/or progressive disease and in all likelihood, the bladder pathways will be affected more due to the development of new lesions or the expansion of old lesions.
If you fail to respond to anticholinergics and/or mirabegron and behavioural techniques you need to have your bladder scanned to see if you have a raised residual volume. The residual volume is the amount of urine left behind after you have emptied your bladder. If the residual volume is greater than 80-100mL you may need to consider intermittent self-catheterisation or ISC. ISC serves two purposes; it increases your so-called functional residual bladder volume allowing more storage space for urine in the bladder; this reduces frequency and urgency. This is can help you if you have to take a long trip or to get through a social activity without having to pass urine. It also helps reduce nocturia or having to get up frequently at night to pass urine. You will be surprised how much better you feel if you get a good nights sleep. Reducing nocturia and improving sleep and improves daytime fatigue.
Another treatment that is becoming increasingly common is botox of the detrusor muscle. This paralyses the muscle turning it into a flaccid bag for urine storage. Almost all pwMS who have detrusor botox are using ISC. In the past, before botox was available, there were surgical techniques that could be used to denervate or remove the nerve supply to the bladder that had the same effect; these techniques are rarely used nowadays.
ISC also removes urine from the bladder. This is important if you are having recurrent bladder infections. The residual urine acts as a culture medium for bacteria and by clearing your bladder you can prevent bladder infections. The opposite can occur. If you are don’t get the ISC technique correct you can introduce bacteria into the bladder that then cause infections.
UTIs and disease progression
The more infections you have, in particular, severe infections, the more likely it is your MS will progress. Therefore if you have recurrent bladder infections you should try and prevent them occurring. How do you do this? Drink lots of liquids; flushing the bladder reduces infection rates. Also alkalinizing your urine by drinking citric acid (citrasoda or lemonade) also helps. Cranberry extract contains proanthocyanidins substance that reduces bacteria from colonising the bladder may help. Please note you need to use the extract and not the juice as the proanthocyanidin concentration in the juice is too low to have an effect.
An infrequently used option is bladder installation with a liquid containing sodium hyaluronate (Cystistat), which replaces the glycosaminoglycan (GAG) layer or glycocalyx of the bladder wall. This makes it difficult for bacteria to stick to the wall to cause infections and is one way of preventing bacterial biofilms, or slime, from forming. Biofilms are increasingly being recognised as a major problem as they prevent antibiotics reaching the bacteria to kill them and act as a nidus for recurrent infections. I have a few patients who have used Cystistat with dramatic results.
Increasing the frequency of ISC may also help reduce recurrent UTIs. Finally using urinary antiseptics may help reduce infection rates. Urinary antiseptics are antibiotics that are concentrated in the urine; they are given in low concentrations so they have little impact on the rest of the body. I tend to cycle their use, every 3-4 months, to prevent the bacteria in the bladder becoming resistant to a specific antibacterial. The agents I use currently are trimethoprim, cephalexin, nalidixic acid and nitrofurantoin.
Nocturia
If nocturia is your main problem using agents to concentrate the urine at night might help. There is a hormone called DDAVP that works on the kidney to reduce it making urine. You can take DDAVP as a nasal spray or tablets. DDAVP can only be taken once a day; if you use it continuously your kidneys will retain water and that can be very dangerous. The latter is called water intoxication; it presents as swelling of the feet and reduces the salt or sodium levels in your blood. If blood sodium level becomes too low it can cause problems. This is why when you start using DDAVP you need to have your sodium levels checked about 4-6 weeks after starting therapy. I am not sure why, but some neurologists are reluctant to prescribe DDAVP. This is a shame as it is a very good drug and can make the difference between getting a good nights sleep or waking feeling tired. You can use DDAVP intermittently and you can use it the day, for example when you need to go on a long trip or for social occasions, e.g. going to the movies or theatre. You can only use DDAVP once a day. The most common side effect is swelling of the feet; it happens in approximately a third of pwMS and is more common in pwMS who are less mobile.
Other advice I give to pwMS is that if you are a smoker then stopping smoking may significantly improve your bladder symptoms; nicotine irritates the bladder. Similarly, reducing alcohol and caffeine consumption may also help; both these agents affect the kidneys and cause them to make more urine. Medically this is referred to as diuresis; both nicotine and caffeine are diuretics. Try to anticipate times when urinary frequency and urgency are likely to be most inconvenient; reducing the amount that you drink beforehand may help. For example, when you go out, don’t drink much for 2-3 hours before you go out. However, do not reduce your total fluid intake to less than 1.5 litres each day. After you have finished passing urine, go back to the toilet again after a few minutes to try to pass some more urine. This is called the double micturition technique, which aims to make sure the bladder is emptied completely.
Conclusion
Finally, if all else fails some pwMS may need to be permanently catheterised. This can be done via the urethra or the lower abdominal wall. The latter is called a suprapubic catheter. Being permanently catheterised sounds awful, but in some pwMS, this drastically improves their quality of life. I have several pwMS who have let bladder dysfunction control their lives and as a result they have become socially isolated. They are typically anxious about being incontinent in public. To avoid this possibility they choose to stay at home. This is clearly unnecessary and with the strategies highlighted above adequate bladder control should be the norm in MS.
In my experience, the biggest hurdle to achieving adequate bladder control is pwMS accepting their bladder symptoms as being part of the disease and living with them.
If you have problems tell your nurse or neurologist; they will be able to help you.
Prof G do you think disability improvement is a reasonable treatment goal?
NEDADI = no evident disease activity and disability improvement
Two weeks ago one of my patients with PPMS, who we treated with off-label subcutaneous cladribine, came for her annual follow-up appointment. Despite being treated with cladribine over 2 years ago she has unfortunately progressed from EDSS 5.5 to 6.5. Her latest MRI brain did not show any new T2 lesions. She asked why we hadn’t scanned her spinal cord. She is desperate for us to find some disease activity so that she can be retreated or preferably offered ocrelizumab. She has a well-off family member who is prepared to cover the costs of ocrelizumab treatment privately. What should I do?
As you know I don’t support private prescribing in the NHS as it undermines the NHS’ founding principles; free at the point of access and equity. However, it is difficult to say no to private prescribing if a patient insists, particularly as there is now a mechanism to do this under the NHS. I am also first a doctor looking after the individual patient and this takes priority over my duty as an NHS employee and guardian of its socialist healthcare ideals.
I didn’t agree to a private prescription for ocrelizumab. Instead, I batted the problem into the long grass and agreed to bring her via our planned investigation unit for an MRI of the spine and lumbar puncture to measure CSF neurofilament levels. If there are new spinal cord lesions and/or a raised CSF neurofilament level then we could potentially look at an additional course of cladribine, off-label rituximab under the NHS, private ocrelizumab or possible recruitment into a clinical trial. I suspect that the MRI will show no new lesions and the CSF NFL levels will be normal. If this is the case then she has NEDA with worsening disability. I did refer her to my blog post on this issue (EXPLAINING WHY YOU GET WORSE DESPITE BEING NEDA) so she could get some understanding of what was happening to her.
During the consultation, she asked me ‘why a friend’s daughter with very bad MS, who had been treated with alemtuzumab, had made such a remarkable recovery?’ Apparently, this young woman had been rendered partially paraplegic from a spinal relapse and after alemtuzumab had recovered function and was now walking almost ‘normally’ again. My patient wanted to know why there was such a difference between herself, someone with PPMS, and her friend’s daughter a young woman with highly-active RRMS.
You may remember the other day I asked you to guess why I was so impressed with the HSCT-MIST trial. Let me try and explain why.
Should we be changing our expectations of what DMTs can offer pwMS? Are we entering an era when the expectation of disability improvement becomes the norm? I certainly hope so.
The most impressive aspect of the recent HSCT-MIST trial was not the NEDA data or the improved safety of HSCT, which are obviously important, but the disability improvement data. During the first year post-HSCT the mean EDSS scores improved from 3.4 to 2.4 vs. a worsening from 3.3 to 4.0 in those on the basket of licensed DMTs. Is this unique to HSCT? How does this HSCT data compare to other treatment options?
The first DMT to show a convincing impact on disability improvement in a phase 3 controlled trial was with natalizumab in the AFFIRM study; at 2 years the probability of a sustained improvement in disability was 30% for natalizumab-treated patients and 19% for patients who received placebo.
The next convincing phase 3 result was with alemtuzumab-treated patients in the CARE-MS2 trial; alemtuzumab-treated patients were more than twice as likely as IFN-β-1a-treated patients to experience 3-month confirmed disability improvement (35% vs 19%).
Unfortunately, the latest HSCT trial did not report their disability improvement data as confirmed or sustained disability improvement at 3 months. The main reason for this was methodological in that patients patients on DMTs had a rescue option of being treated with HSCT. However, in the first 12 months, 12/55 (22%) of patients on DMTs compared to 38/55 (69%) who were treated with HSCT had an improvement in their EDSS. Based on the final data set I suspect that in a large proportion of the HSCT patients the improvements were sustained.
What about the new kids on the block, i.e. ocrelizumab and cladribine? Unfortunately, we don’t have published data on cladribine, but I will try and rectify this and will ask for the analysis to be done. However, the phase 3 pooled OPERA data of ocrelizumab has been published; 21% of ocrelizumab-treated patients had disability improvement confirmed after at least 12 weeks compared to only 16% of IFN-β-1a-treated patients.
So the league table for disability improvement of HSCT over alemtuzumab, over natalizumab, followed by ocrelizumab seems to mirror the brain atrophy or end-organ damage data. Are you surprised? I am not. A large driver of disability improvement is reserve capacity, i.e. brain reserve or put simply the size of your brain, which predicts and provides the substrate for recovery. This is another reason why you would want your MS treated early and just maybe you would want to flip the pyramid and go for the DMTs that offer you the best chance of disability improvement.
Hidden in this data may be a clue about the pathogenesis of MS. What differentiates HSCT and alemtuzumab from natalizumab and then from ocrelizumab? Could it be the transient depletion and reconstitution of the T-cell compartment?
Joanne Jones and her colleagues from Cambridge showed that among trial participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity on-trial, disability improved after alemtuzumab but not following interferon β-1a. They suggested that this disability improvement after alemtuzumab could not be attributable to its anti-inflammatory effects and suggested that T lymphocytes, reconstituting after alemtuzumab, permit or promote brain repair via the production of growth factors in particular brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF) and ciliary neurotrophic factor (CNTF). If their hypothesis holds out then this may be another reason why NIRTs (non-selective immune reconstitution therapies) outperform SIRTs (selective immune reconstitution therapies) in going beyond NEDA, i.e NEDADI. And just maybe you need these cells to traffic to the central nervous system to deliver these growth factors.
Another piece of the puzzle is the positive effect alemtuzumab has on the MRI metric called magnetization transfer ratio or MTR, which is a measure of tissue integrity. In a small study, the mean MTR fell in 18 untreated MSers in normal-appearing grey and white matter. Conversely, mean MTR was stable in 20 alemtuzumab-treated MSers, which suggests alemtuzumab protects against tissue damage. This MTR data mirrors the clinical observations and is congruent with some of the basic science. Wouldn’t it be nice to do an experiment of using natalizumab post-alemtuzumab to see if by blocking T-cell trafficking we blunt the alemtuzumab-associated improvement in disability, i.e. to test whether T-cell trafficking is required to drive repair mechanisms?
So what do I tell my patient? Do I tell her that the reason why she has not improved is that she is older, has more advanced MS and hence less reserve capacity to allow disability improvement? Or that we may not have tackled the root cause of her MS with subcutaneous cladribine? I stuck to the former explanation as the latter is simply a hypothesis that needs more thinking, more debate and some new experiments to establish if the treatment hierarchy in relation to end-organ damage and disability improvement is based on the different modes of action of our DMTs.
Despite the reasons behind these observations we are now entering an era were disability improvement is not an unreasonable expectation for pwMS, provided they are treated early and with high-efficacy DMTs.
How many you have been told about disability improvement on DMTs?
CoI: multiple, please note that I am a co-author on the natalizumab, alemtuzumab and ocrelizumab disability improvement papers.
Prof G are we being lulled into a false sense of security by being told that we have no evident disease activity (NEDA)?
A patient of mine, who I have been looking after now for over 11 years, asked me in clinic a few weeks ago why despite being NEDA for 6 years, on a highly effective maintenance DMT (fingolimod), has she gone from being able to run 5-10 km to needing a stick and barely managing to walk from the Whitechapel Underground Station to my clinic (~200m), without having to stop and rest?
What this patient doesn’t know, despite no new visible T2 lesions, is that she has developed obvious, to the naked eye, progressive brain atrophy. This particular patient prompted me to write a few blog posts to try and explain what is happening to her brain. Before reading the remainder of this post you may want to read the following posts:
An important question in relation to this patient is why do some DMTs have such a profound impact on end-organ damage markers, in particular, brain volume loss and others do not? Not all DMTs are made equal when it comes to preventing, or slowing down, brain volume loss.
At the top of the league table are alemtuzumab and HSCT (~0.2-0.25% loss per annum). Both these treatments are NIRTs (non-selective immune reconstitution therapies). Natalizumab is next with an annual brain volume loss in region of 0.25-0.30% per annum. Ocrelizumab (anti-CD20) comes fourth with a rate of brain volume loss of ~0.30-0.35% per annum. Fingolimod 5th at ~0.4% per annum. Cladribine has a rate of loss of brain volume of ~0.55% per annum with the other runs after that.
For me, the disappointment are the anti-B cell therapies, ocrelizumab and cladribine. Despite these DMTs being very effective at switching off new focal inflammatory lesions (relapses and new T2 and Gd-enhancing lesions) their impact on end-organ damage is only moderate. These observations have convinced me more than ever that focal inflammation is not MS, but simply the immune system’s response to what is causing MS. The latter hypothesis is what I have been presenting as part of my ‘Field Hypothesis’ for several years on this blog.
What these observations are telling me is that peripheral B-cells are a very important part of the immune response to the cause of MS, but they are not necessarily involved in driving the true pathology, which is causing the progressive brain volume loss. The caveat to this is that anti-CD20 therapies and cladribine may not be eliminating the B-cells and plasma cells within the CNS, which is why we need add-on treatments to try and scrub the brain free of these cells to see if the brain atrophy rate ‘normalises’. This is why we are starting a safety study this year of an add-on myeloma drug to target the CNS B-cell and plasma cell response to test this hypothesis.
What does this mean for the average person with MS? Firstly, you may not want to dismiss alemtuzumab and HSCT as a treatment option. These NIRTS differ from anti-CD20 therapies and cladribine in that they target both B and T cells. We may need to target both these cells types to really get on top of MS. I am aware of the appeal of anti-CD20 therapies and cladribine; they are safer and easier to use because of less monitoring, however, this may come at a cost in the long-term. The SIRTs (selective IRTs) may not be as good as the NEDA data suggests. Please remember that once you have lost brain you can’t get it back.
The tradeoff with alemtuzumab and HSCT is the frontloading of risk to get the greatest efficacy over time. Choosing a DMT on a rung or two down on the therapeutic ladder gives you better short-term safety and makes the lives of your MS team easier, because of less monitoring, but at a potential long-term cost to your brain and spinal cord. This is why to make an informed decision about which DMT you choose is a very complicated process and subject to subtle and often hidden effects of cognitive biases. The one bias I am very aware of is the ‘Gambler’s Dilemma’, be careful not to be lulled into a false sense of security by your beliefs; most gamblers lose.
Over the last few years you may have seen a theme developing in my thinking as we move the goalposts in terms of our treatment target beyond NEDA-3 to target end-organ damage, i.e. brain volume loss, T1 black holes, the slowly expanding lesions (SELs), neurofilament levels, cognition, sickness behaviour, OCBs, etc. Our treatment aim should be to ‘Maximise Brain Health’ across your life and not just the next decade. Please stop and think!
When I was preparing this post I dropped Prof. Doug Arnold an email about the impact of alemtuzumab and HSCT on the slowly expanding lesion or SEL. Unfortunately, these analyses have not been done despite good trial data sets being available for analysis. He said it was a resource issue; i.e. a euphemism for money and permission to do the analyses. For me, these questions are the most important ones to answer in 2019. Wouldn’t you want to know if alemtuzumab and HSCT were able to switch off those destructive SELs in your brain? Knowing this may impact your decision to go for the most effective DMTs; frontloading risk to maximise outcomes in the long term.
What should I advise my patient; to stay on fingolimod or to escalate to a more effective DMT?
The following articles are the important ones for you to read or at least be aware of:
BACKGROUND: A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy.
OBJECTIVE: We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT.
METHODS: Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions.
RESULTS: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was -0.23% per year, consistent with the rate expected from normal aging.
CONCLUSION: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.
OBJECTIVE: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).
METHODS: The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II).
RESULTS: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a.
CONCLUSIONS: Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS.
CLASSIFICATION OF EVIDENCE: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.
BACKGROUND: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment.
OBJECTIVE: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab.
METHODS: A total of 42 relapsing-remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated.
RESULTS: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year.
CONCLUSION: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.
Prof G what happens to MS disease activity if you stimulate T-cells?
About 2 years ago I attended a grand round during which a patient with a history of RRMS had had a catastrophic relapse after receiving ipilimumab for metastatic melanoma. The patient has a massive brain stem relapse and her MRI showed multiple Gd-enhancing lesions with several pseudotumoral lesions. She was in a bad way. Interestingly, this case was not unique as a very similar case had been published. In addition, there are series of other examples of ipilimumab and other immune checkpoint inhibitors exacerbating and/or triggering autoimmune diseases including an MS-like disease. I say MS-like because we don’t know for sure if these cases will turn out to have classic MS on biopsy, or at post-mortem, to prove they have definite MS according to a conventional definition of the disease.
Ipilimumab belongs to the class of drugs called ‘checkpoint inhibitors’ that are designed to remove one of the immunological brakes that control T-cell activation. Ipilimumab is one of many T-cell stimulants that have revolutionised the care of patients with various different cancers. Ipilimumab is a very smart drug it blocks CTLA-4, a cell surface molecule on T cells, which normally blocks or downregulates T cell activation when it binds to CD80 and CD86 on antigen-presenting cells. Ipilimumab enhances the anti-tumoral response while increasing the likelihood of autoimmunity.
So what has this really got to do with MS? Well, these cases are telling us in a not so subtle way that by stimulating T-cells we can exacerbate MS. In other words, T-cells are probably still active in established MS. What this experiment is not telling us is which population of T-cells is the culprit as CD4+, CD8+ and T-regulatory cells express CTLA-4 and are hence affected by Ipilimumab. Nor is it telling us about the APC side, which APC is stimulating the T-cells. Is it the B-cell, the macrophage/microglia or another APC?
The moral of this story is that it takes two to tango; the T-cell and its APC. The question is which APC is the preferred partner for the T-cell in MS. Based on the evidence the B-cell seems to be the dominant partner, but who knows in the presence of peripheral B-cell depletion other less dominant partners may take to the floor.
56-year-old male, diagnosed in December 1997 with RRMS. Treated with glatiramer acetate in February 1998. Relatively good response to GA with only sensory relapses. In 2005 methotrexate was added. His MS stabilized and he was free of relapses from 2005 to 2013 with a slight increase in disability from an Expanded Disability Status Scale (EDSS) score of 1 to 1.5. In September 2009 diagnosed with melanoma. He had a recurrence in November 2012 with metastases to soft tissue and lymph nodes. He was started on ipilimumab. Methotrexate and glatiramer acetate were stopped prior to initiating ipilimumab. Within one month, he presented with subacute onset of left lower extremity hemiparesis, gait dysfunction and ataxia. An MRI revealed a new left centrum semiovale enhancing lesion consistent with active demyelination. His symptoms improved with high dose methylprednisolone. Ipilimumab was continued. In May 2013 he was readmitted for transient left-sided weakness and ataxia. MRI revealed an enhancing lesion in the right corona radiata. Follow-up imaging revealed a second enhancing lesion in the right frontal lobe and he was restarted on glatiramer acetate and steroids.
I have always wondered why the genomic experts in the field of MS haven’t been able to sort out why specific human leukocyte antigen (HLA) subtypes increase your risk of getting MS and others don’t.
HLA or human leukocyte antigens are the so-called signposting proteins that antigen presenting cells (APCs) use to communicate with T-cells. The APCs continuously sample the environment and present small peptides in their HLA molecules to T-cells. The HLA molecules interact with the so-called T-cell receptor (TCR) and if the peptide (message) that has been loaded in the HLA groove (signpost) and TCR, which acts as a molecular reader, fit perfectly it tells the T-cell that it should go on the attack. In the context of MS, this attack is considered to autoimmune or dysfunctional and against a self-peptide. However, the attack could be entirely appropriate and targeted against a foreign protein or a self-protein that has been altered by a process called post-translational modification. Interestingly, smoking and solvents, exposure to which are both risk factors for developing MS, are two environmental exposures that are known to cause post-translational modifications of proteins.
The following YouTube animation shows you an example of how a TCR (reader) interacts with a specific HLA molecule (signpost) and the peptide (message) in the groove of a specific HLA molecule. By watching this video you may appreciate how specific this interaction really is.
The most important genetic risk factor for deevloping MS is the so-called HLA-DRB1*15:01 molecules. If you have one copy of this gene your risk of getting MS is ~3X greater than someone without this gene. If you have two copies your risk of getting MS is about ~6X greater. In other words from a genetic perspective, you don’t want to have the HLA-DRB1*15:01 signposts.
It turns out that there, not all HLA-DRB1*15:01 molecules are made equal and that if you have the African variety, compared to the European variety, your risk of getting MS is 3x lower. Interestingly, the African and European varieties of the HLA-DRB1*15:01 genes differ in their sequence in a way that would affect the so-called peptide binding groove of the HLA molecule. This would mean that they would bind peptides differently and hence affect the way that T-cells may or may not be activated. How interesting?
The African variety of HLA-DRB1*15:01 is presumably older and the genetic change in HLA-DRB1*15:01 that is now known as the European variant must have been selected for after man left Africa and migrated into Europe. The most likely evolutionary selection pressure for this selection was repeated exposure to an infection, which selected for this variant, with the later consequence of being an increased risk of getting MS.
What is the significance of these findings? It is telling us that MS risk is related to a very specific HLA-DRB1*15:01 variant and this variant, by definition, must be interacting with a specific family of peptides or possibly a single peptide in our environment or body. Wouldn’t it be great if we could find this peptide or family of peptides? It could potentially lead us to the cause of MS.
It is important to realise that the HLA-DRB1*15:01 association with MS, and these new findings in relation to the African and European variants, is telling us that the T-cell must be the central player, or conductor, in the pathogenesis of MS and must be upstream of the B-cell. I have mulled over this for many years and I can’t think of another way of interpreting these results. Do you agree?
Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.
Is targeting the B-cell sufficient to get on top of MS or do we need something extra?
I spoke at the MS Nurses’ MS@TheLimits2019 meeting at the Royal College of Physicians yesterday. My brief was to cover the role of B-cells in the pathogenesis of MS and to review the converging evidence that supports B-cells being the central player in the pathogenesis of MS.
It is clear that depleting B-cell therapies are very effective in controlling relapses and MRI activity. With a very favourable safety profile and relatively low treatment and monitoring burden, B cell therapies are likely to become one of the most widely prescribed classes of DMT. However, B-cell therapies don’t match HSCT, alemtuzumab and natalizumab when it comes to downstream end-organ damage markers, in particular, brain volume loss. Why? I wish I knew. But if I knew the answer to this question I would have a pretty good idea about the cause of MS.
A clue may be in the ‘Field Hypothesis‘. It is clear to me that relapses and focal MRI activity are not the primary events in MS. Focal inflammation is not MS. Focal inflammation is in response to what is causing MS and the cause is likely to be something in the CNS. Focal changes occur in the white matter weeks to months before you get a Gd-enhancing lesion. When you stop natalizumab and allow re-trafficking of lymphocytes you get rebound disease activity way and above what one would expect from pre-treatment baseline levels of disease activity. What is happening in the brain, or field, of these patients to trigger such a vigorous inflammatory response? Could it be a virus? Importantly, B-cells appear to be needed for the rebound response. Rituximab, and I suspect ocrelizumab, are very effective in preventing rebound. However, as both these agents target a small subset of T-cells you can’t claim categorically that the rebound is only driven by B-cells.
The difference between HSCT, alemtuzumab and natalizumab and the anti-B cell therapies (rituximab, ocrelizumab and possibly cladribine) is the former take out or inhibit trafficking of both T & B cells. As HSCT and Alemtuzumab have the best data in relation to long-term remission, or potential cures, you have to conclude that you need to target both B cell and T cells (substantial peripheral depletion) if this is your treatment aim.
Please note that I classify cladribine as a B-cell depelter and not a dual B and T cell depelter. The level of T-cell depletion with cladribine is modest at the licensed dose (~50%) which is not sufficient to put it into the same class as alemtuzumab and HSCT. This is one of the reasons why I refer to cladribine as being a SIRT (selective immune reconstitution therapy) and the others as NIRTs (non-selective immune reconstitution therapies).
I have always made the point that to treat MS you need much more than an anti-inflammatory and that you also have to have neuroprotective therapies and potentially remyelinating agents on board as well. If you have disabilities we need to be thinking about neurorestorative therapies and finally you need to target lifestyle and wellness to tackle the issue of comorbidities and ageing.
So in short, targeting B-cells is important, but not sufficient to get on top of the shredder.
You will see that a large part of my talk was covering the link between EBV, B–cells and MS. The B-cell hypothesis at least strengthens the case for EBV being the cause of MS and the need for an EBV vaccine for MS prevention trials. Please don’t forget that EBV lives inside memory B cells and hijacks the B cell’s biology in many ways that have potential relevance to MS and other autoimmune diseases.
My talk will be available online in a few weeks to help you interpret my presentation. In the interim you can download my talk from my slide sharing site.
Happy New Year! In response to a comment yesterday I produced the following overview of some of Barts-MS’ activities for 2018. It makes me very proud to be part of the team and I would like to thank them all for all their hard work and perseverance.
I would like to think of 2018 as the year of the #HashTag.
Some of our long-running social media campaigns have started to deliver returns on the time and effort that have gone into them. All of these have been linked to a particular #HashTag.
In short Barts-MS’ 2018 activities can be classified into five categories which are research, services, policy, education and PPI (patient-public involvement).
1. Research
#ThinkHand – We continued to make a strong case for our #ThinkHand campaign with numerous research outputs. These are all being used to support further work in this area. I am the principal investigator for ORATORIO-HAND a phase-3b study of ocrelizumab in PPMS that will include patients with an EDSS of up to 8.0. The primary outcome is the 9-HPT. In parallel, DrK has been working hard to get an NIHR funded trial off the ground called CHARIOT-MS. DrK has shepherded the grant through round 1 and is waiting to hear whether or not the study will get funded. CHARIOT-MS is a study of oral cladribine in advanced MS targeting both SPMS and PPMS with the primary outcome being the 9HPT. If there is one person in our group who deserves an award for resilience and perseverance it is DrK; he has doggedly stuck to the task. There will be much celebration at Barts-MS if he gets his just rewards for all his hard work over the last few years. More importantly, CHARIOT-MS will become a beacon of hope for people with advanced MS.
#SelfMonitoring – Nicholas Dubuisson completed a herculean meta-analysis to analyse inclusion criteria used for progressive MS trials. In summary, it shows what a mess the field is in when it comes to identifying who is worsening or progressing prior to being recruited into progressive clinical trials. We have used this meta-analysis to make the case for using self-monitoring to document worsening in the 12-24 month prior to trial recruitment. In response to this, we have been gradually building our suite of online web apps to empower and activate the MS community to do just this.
#under&over – Alison our design researcher developed a hand and upper limb rehabilitation tool called under&over, which was launched at ECTRIMS2018 in Berlin. Alison has been successful in getting a grant to test whether or not under&over will work as a remote rehab tool.
#ThinkCognition – I have been pushing the concept of MS being a preventable dementia for several years and that by focusing on cognition early on in the course of the disease we would get the MS community to adopt the early-effective treatment paradigm. One hypothesis that I proposed several years ago came to fruition this year; i.e. that pwMS who are able to learn on a cognitive test do better than poor-learners. This analysis was done with Maria-Pia Sormani using the combined FREEDOMS fingolimod data set.
#ThinkSocial – You will notice some early activity from our group on social capital as a potential predictor of outcomes in pwMS. We have been very fortunate to have Saul Reyes a Colombian neurologist join us an ECTRIMS fellow for one year. Saul will be studying social capital in MS. The other excellent news is that the Horne Family Foundation has awarded us a grant to study whether or not our PPI programme increases social capital and if it does will this increase the quality of life of pwMS and reduced healthcare utilization. Ultimately, we want to be able to do long-term studies to assess whether or not increasing social capital improves outcomes for pwMS. An interesting point worth noting is that the UK government has just appointed a loneliness minister to address social isolation at a population level. I interpret this as a sign that our #ThinkSocial campaign is of the moment.
#PreventMS – The MouseDoctor and I left Queen Square to move to Barts and The London School of Medicine and Dentistry (Queen Mary University of London) in 2006. One of the main drivers for me personally was to shift my long-term research focus on MS prevention. This year saw the activation of a priming grant to set-up a Preventive Neurology Unit that includes a group working on MS. We were able to get Dr Ruth Dobson back to QMUL to lead the MS Prevention programme. We have a lot of activities planned under this banner for 2019 and beyond. We will keep you posted on developments in this space, but you can get the gist of things to come from our recent blog posts on ‘proving EBV is the cause of MS’ and ‘Why do I have MS?.. Because you have a common virus?’.
#CharcotProject – We finally got publish the results of INSPIRE trial and our #CrowdaCure EBV saliva shedding project. The saliva data has been instrumental for powering our FamV study, which we hope to start in the next few months. Please note the contrary to some commentators the #CharcotProject is alive and kicking.
2. Services
#OffLabel – We published our own experience with using off-label subcutaneous cladribine in MS and provided anecdotal evidence, using case studies, that it will work in people with more advanced MS. The latter has been vital in supporting our CHARIOT-MS grant application. Whether or not these publications will get other centres in the UK and other countries to follow our lead is a moot point. Interestingly, we have had a few centres requesting our off-label protocol so there may be the gradual rumblings of an off-label movement starting.
#AtraumaticLP – We continue to promote using lumbar punctures and CSF analysis to monitor MS. Central to this is our LP service that now only uses atraumatic or non-cutting needles to reduce the complications of LPs in particular post-LP headaches.
#EndOrganDamage – Our lab service measuring CSF neurofilament levels more than trebled last year. Sharmilee and Lucia have done a remarkable job. At least four other UK centres are regularly requesting CSF NFL levels via our laboratory. We also have the peripheral blood assay working and are part of an International consortium to validate the assay. I suspect we may move from CSF to peripheral blood monitoring very soon.
#NAbs – We are in the process of validating our anti-alemtuzumab and other anti-drug antibody assays. We know NAbs are an important issue and explain why some pwMS fail to respond to biological therapies. NAbs, in particular, those targeting alemtuzumab, are also a window into the immunology of the drug and may be telling us why pwMS treated with alemtuzumab get so many secondary autoimmune diseases. Watch this space!
3. Policy
#OffLabel & #EssentialMedicine – In 2014 whilst I was on my 6-month sabbatical we formulated the Barts-MS Essential Off-label DMT list. This was to address limited access to DMTs in resource-poor countries. Off-label subcutaneous cladribine is one of the drugs on this list. We soon realised that trying to sort out access to essential medication was a problem and task too big for Barts-MS. I was fortunate to be invited to present some of our ideas to the board of the MSIF in 2015 and as some of our ideas dovetailed with their 5-year strategy they were able to take up the challenge. I was honoured and privileged to be asked to co-chair the MSIF’s WHO Essential Medicines panel with Brenda Banwell and to help prepare and submit a proposal to the WHO to get a limited number of DMTs on the WHO Essential Medicines List. We successfully submitted an application in early December. This was a mammoth task as it involved many different stakeholders and I want to thank the MSIF for making this a reality. Fingers-crossed!
#BrainHealth – Our Brain Health initiative turned three last year. We have continued to promote #BrainHeallth awareness in the 3-years since we launched the original policy document at ECTRIMS-2015 in Barcelona. However, as information is not sufficient to change behaviour we made progress in developing our international quality standards and have piloted them in three countries. In 2019 we will be focusing on disseminating the quality improvement tool and developing a #PatientActivation programme.
#Women4MS – In collaboration with Alasdair Coles, we highlighted the inequities in relation to women at the top table in the field of MS. Our blog posts and subsequent publication has set off a chain reaction and a response letter by female academics, who make the point that gender inequality occurs despite the availability of a substantial number of successful senior female academic neurologists and neuroscientists worldwide. DrRuth and her team have done some data trawling to highlight the problem further and these data will be published later this year.
#Run4MS – This is an initiative using parkrun programme to get pwMS and HCPs more active. #Run4MS is an ambitious, but important, initiative and is being run by the MS Trust.
#MS_is_1_and_not_2_or_3_diseases – We have continued to challenge the current dogma and promote MS as being one disease.
4. Education
#MSPreceptorship – We continue to run our MS Preceptorships that are designed to teach people about MS and the modern management of the disease.
#MSAcademy – I am the director of the MS Academy. This programme has expanded and included a meeting to tackle variance in the provision of MS Services in the UK. If you want to participate in the MS Academy please register for one of the upcoming courses.
#MS@TheLimits – I co-chaired our second MS@TheLimits meeting in London in November. Feedback from the delegates was remarkably good and we will endeavour to make this an annual event. For those of you who are interested, all the talks are now online, including Prof G taking a battering in a debate. To be fair I had to prepare my arguments in a few hours on the day of the debate as one of our debaters had to pull out at short notice.
#triMS-Online – We finally managed to get our virtual online conference started. Our first event was very well received and addressed all our objectives. The idea for this meeting was germinated and developed on this blog; so thank you. Who said social media was a one-way street? We learn as much from you as you learn from us. Please note that more than half of the steering committee of triMS.online are women and it includes many young people from all over the world; this is no accident.
#ECTRIMS2018 – We hosted a #ClinicSpeak stand at ECTRIMS; this year with a focus on #SelfMonitoring. The MouseDoctor and Sharmilee did their annual MS Hangout that is a real hoot and worth watching. We also arranged and ran the annual ECTRIMS Burning Debate. The motion debated was “The new McDonald diagnostic criteria make them difficult to use in clinical practice”. This year it was an all female event, which was to compensate for the all-male affair in 2017.
#MSFellowships – We continue to encourage and accept young trainees to our centre. This year was no exception and included a very bright and energetic Erasmus exchange student.
5. Patient-public Involvement or PPI
#DigestingScience – Alison and her team have continued to disseminate her Digesting Science programme in the UK and globally. The Digesting Science packs have been translated into two other languages. As this programme targets children of pwMS, we will be embedding it our PPI programme for #PreventMS going forward.
#ResearchDay – This year we decided to take our research day to the Hebrides and had a very successful meeting in Stornoway. The Stornoway talks are all online. Unfortunately, the London MS Research Day didn’t happen for a second year in a row. We need to do something about it. Any suggestions?
#ResearchBlog & #SocialMedia – We continue to run our blog with almost daily postings. I took a break from the blog to focus on grant writing but will make an effort in 2019 to post more frequently. I increased my social media activity to try and compensate, but there is not much you can say in 280 characters, which is not ideal
#ThinkHand – We held a very successful #ThinkHand event in London in Feb last year to celebrate hand function in pwMS. Our #ThinkHand event was bigger than simply an awareness campaign and we managed to get wider media coverage and bring several important stakeholders on board to support #Chariot-MS
What about 2019 and beyond?
The above summary is only a brief overview of some of #BartsMS’ activities in 2018. The list is not exhaustive but does give you an idea of what we are trying to achieve. 2019 will be more of the same, with an emphasis on the following #HashTags:
