I am taking stick from many readers about my stance on HSCT. I implied in a comment yesterday that I would seriously consider it as a first-line treatment if I had MS, but in reality, I don’t offer or support HSCT for my own patients with MS as first-line therapy. Some readers are accusing me of double-standards. Should I walk the talk and put my head above the parapet or keep quiet? I have a potential solution; read on …..
The issues around HSCT are complex. HSCT is not a mainstream treatment for MS but will become so when more evidence emerges about its relative efficacy and safety when compared to other licensed DMTs. To address this question we will hopefully be starting a head-2-head trial of alemtuzumab vs. non-myeloablative HSCT in the near future.
At the moment HSCT is available to pwMS under the NHS, but not as first-line therapy. Why? It positioning as a 2nd- or 3rd-line therapy was made by consensus, albeit an HCP consensus, and the current opinion is to limit NHS access to HSCT to pwMS who have failed at least one high-efficacy DMT. I personally don’t agree with this. Provided pwMS are well informed and understands the risks of HSCT and are prepared to take the risks they should be able to have HSCT. There is no doubt that it will be cost-effective; as a one-off treatment, HSCT costs between £28,000 and £30,000. When you compare this to the annual and cumulative costs of some of the other DMTs HSCT becomes very appealing. The downside as always are the risks, and some would argue the risks are too great. Who should be taking the risks; the person with the disease or the HCP? I know where my allegiances lie.
When you have a disconnect between the needs, or implied needs, of the MS community, and the position of the NHS and/or the HCPs there is a potential solution for this problem called a Citizens’ jury. This is when a group of people from the general public (not people with MS or vested interests) decide policy on behalf of pwMS and HCPs; in other words, citizens decide if the NHS and/or HCPs are right to withhold an effective treatment from pwMS based on its costs and/or safety profile. At the moment most CPs feel HSCT is too risky to be a mainstream treatment for MS.
What I am proposing is that we set up a Citizens’ jury that looks into the question of whether or not HSCT should be available for pwMS, who have active MS, as a first-, second- or third-line therapy. If the jury says ‘yes’ then the NHS should create the necessary capacity to deal with the needs of the MS community. I think the NHS may support the results of a Citizens’ jury as it is win-win for them. Firstly, they will be viewed as being proactive in supporting MSers wishes and if they have to make HSCT widely available as a treatment for MS it will save the NHS money; potentially lots of money. From a person with MS’ perspective it will also be a win-win; i.e. (1) they will have the option of being treated with potentially the most effective DMT under the NHS and (2) they won’t have to cover the private expenses of having to travel abroad to have HSCT. Accessing HSCT under the NHS will also make it more equitable. What about the HCP or neurologist? Is it a win-win for them? Or a lose-lose for them?
Interestingly there was a very well written opinion piece in last week’s BMJ on the use of Citizens’ juries. It is worth a read.
….. Citizens’ juries (or community juries or citizens’ assemblies) aim to give ordinary people a role in democratic decision making. They usually consist of 12-20 randomly selected and demographically representative people, but some have had as many as 100. They explore difficult policy questions for government, charities, or think tanks. They differ from focus groups in that participants should be given reliable information and time to deliberate.
…. Malcolm Oswald, director of the Citizens’ Juries community interest company, a social enterprise supported by the University of Manchester, says, “Citizens deliberate among themselves, and, as they become better informed over several days, their views often change.”
…. They are particularly helpful for considering controversial and value-laden questions. For example, the Irish parliament formed a 99 member jury to advise elected representatives on ethical and political dilemmas including abortion, climate change, and provision for an ageing population.
…. What are their strengths?
Citizens’ juries involve the public in decision making, providing diverse experiences and perspectives, and the process can be thorough.
What do you think? Should we lobby the NHS to have a citizens’ jury on the issue of HSCT as 1st-line treatment for MS?
Help! How do I manage progressive brain atrophy in a patient who is NEDA-3?
End-organ damage is a catch-all phrase for the degeneration of the brain; it occurs as part of the ageing process that some consider pathological and others as a normal fact of life. I have hinted that I consider it both because end-organ damage is potentially modifiable via lifestyle modifications and pharmacological interventions. If it was a normal process it should not be modifiable. How can you be more normal than normal? Making ageing a disease also has political ramifications, for example, it will almost certainly incentivise Pharma to develop treatments for ageing.
In MS end-organ damage is massively accelerated by the MS disease process itself, i.e. inflammation and demyelination, and from delayed downstream processes triggered by inflammation, for example, energy failure, microglial activation, ongoing inflammation driven by antibodies, possible slow viral infection and its consequences and comorbidities. It is clear that all people with MS will have end-organ damage, but what can we do about it? To be honest, apart from early treatment to prevent damage, we haven’t got an evidence base about how to manage this problem in MS.
As an example, I saw a patient earlier this week. He has relapsing-remitting MS diagnosed in the mid-2000s and started on interferon-beta (Avonex). He also has type 1 diabetes which he developed when he was 14 years of age, 8 years before he was diagnosed with MS. His diabetes was poorly controlled initially but is now well controlled on an insulin pump. He has renal (proteinuria), eye (retinopathy) and hypertension as complications of his diabetes. His hypertension is controlled on medication. He has been relapse-free and his MRI has not shown any obvious new lesions over the last 6 years; i.e. he is NEDA-3. He does not smoke, but he drinks between 3 and 4 units of alcohol per day. He was referred to me because he is sick and tired of injecting himself with interferon and he has heard of a new drug called ocrelizumab. He wants to be switched to it because is more efficacious and only give every 6 months. His treating neurologist said no, hence his referral to me for a second opinion.
When I went through his history it is clear he has had no relapses in the last 6 years and is fully functional and working full-time. I reviewed his MRIs and I agree he has no new lesions over the last 6 years, but he has developed quite profound and progressive brain atrophy over this timeframe; he is definitely not NEDA-4. What do I do?
Do I switch him from interferon-beta to ocrelizumab? Or do I leave him on Avonex, which is doing its job and rendering him NEDA-3?
If I do switch him to ocrelizumab, will it normalise his brain volume loss? Will he become NEDA-4?
What is causing his brain volume loss? MS, hypertension, diabetes, alcohol or something else?
Do I tell him about his gross brain atrophy, which he is blissfully unaware of?
Do I offer him a formal cognitive assessment to see if he has cognitive impairments? If he has a cognitive assessment and they come back abnormal, which they are likely to, how do I tell him? Will knowing he cognitively impaired affect his management?
Do I offer him a lumbar puncture to measure his spinal fluid neurofilament levels?
Do I recommend any add-on off-label treatments that may help?
Or do I just take the easy option and send him back to his neurologist with a recommendation to leave things as is?
Can I suggest we debate these issues over the next few days and I can then potentially do a live webinar on the issue of end-organ damage and how to handle the problem of progressive brain volume loss on DMTs when you are NEDA-3.
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.
Do we need to include cognition as a treatment target in multiple sclerosis?
In every clinic, I do patients with MS complain of cognitive symptoms. Either it is increasing forgetfulness, difficult multi-tasking, the inability to learn and use a new technology or cognitive fatigue.
Case study: One of my high functioning patients, who worked in a large City law firm, simply could not keep up and was recently forced to take early retirement because of her MS. She had been interferon-beta-1b for 12 years but had stopped treatment about 7 years ago when she had moved to London. Her MRI showed a highish lesion load and severe brain atrophy. She had had a few relapses on interferon-beta in the early years, but her neurologist decided to leave her on interferon-beta. Back then this was normal practice; we didn’t expect interferon-beta to render you relapse-free. Interferons were only meant to reduced attack rates by about a third and severe attacks, i.e. those requiring steroids and/or hospital admission, by about a half. The only alternative when this patient was having relapses on interferon-beta was glatiramer acetate; please remember this was pre-natalizumab era. Apart from her cognitive problems, this patient had mild unsteadiness of gait, but this had not affected her walking distance and she was still able to do yoga several times per week. To help with her unemployment insurance claim I requested a formal neuropsychological assessment and she was documented to have profound cognitive deficits across multiple domains. The conclusion based on these tests was that she would never be able to have meaningful employment again; at least not in the knowledge economy When I took a detailed history it was clear that she had had progressive cognitive impairment over at least 7-10 years. In other words, she had secondary progressive MS manifesting as progressive dementia.
You must not underestimate the impact MS has on cognition. Cognitive problems can be there from the start; approximately a quarter of people with a radiologically isolated syndrome (RIS) or asymptomatic MS already have cognitive impairment. The proportion with cognitive impairment just gets higher the longer you have the disease. What is driving cognitive impairment is almost certainly grey matter pathology, both in the cortex and deep grey matter, which is not detected with our current monitoring tools.
In the analysis below, of the pivotal phase 3 fingolimod trials, we showed that not being able to improve on the Paced Auditory Serial Addition Test (PASAT) at baseline predicted a worse outcome. The PASAT is a very sensitive cognitive test that used to part of the battery we called the MS Functional Composite (MSFC). The PASAT is not very nice to do and has now been replaced by the SDMT (symbol digital modality test).
When you start doing cognitive screening tests such as the PASAT and SDMT you tend to improve the scores due to a learning effect. We hypothesised that pwMS who couldn’t learn i.e. were unable to improve their PASAT scores at baseline would do worse. This is exactly what we found and we noted it regardless of treatment allocation; i.e. whether you were on fingolimod or placebo. Poor learners were older, had a higher disability score at baseline, smaller brains and higher lesions volumes on MRI; i.e. they had reduced cognitive reserve. The depressing point about this analysis was that even the poor learners on fingolimod did badly; it was if they were already primed to do badly and that starting a DMT had a limited impact on the outcome. Active MS in the past had primed their brains to continue deteriorating; previous damage or a new type of MS lesion, possibly SELs (slowly expanding lesions) was driving their worsening.
The message here is that it is very important to prevent the ravages of MS by treating as early and effectively as possible. In some pwMS, this is easy because you present early before too much damage has accrued. In others, you may have longer asymptomatic periods during which you have already acquired a lot of damage. Regardless of what group you are in, you need to seriously consider getting on top of your MS disease activity as soon as possible to prevent further damage.
It is clear from the Sormani meta-analysis (article 2 below) that you do best on DMTs that have the greatest impact on inflammatory activity (new MRI lesions) and those that reduce brain volume loss the most. This is why flipping the pyramid and going for the most effective DMTs first-line is a very appealing treatment strategy; particularly those that ‘normalise’ brain volume loss.
This study also raises the question about whether or not we should be monitoring cognition in routine clinical practice? This topic is a hot potato and gets discussed and debated all the time. At the moment I think most neurologists don’t agree with doing routine cognitive testing, because of the lack of evidence in terms of treatments that impact on cognition. This, however, may change when siponimod gets licensed. It is clear in the siponimod trial that siponimod delayed cognitive worsening compared to placebo. The following is the siponimod data that was presented at the AAN and EAN last year.
I believe that everyone with MS should have the option of monitoring their own cognition. If your cognition is improving and/or is stable that is good news. If, however, cognition is worsening then a frank discussion needs to be had about why it is getting worse and can anything be done about it. There are many reasons why pwMS may have worsening cognition and some of these are treatable. This is why we have developed an online cognitive test, which we are currently validating, to allow self-monitoring of cognition. If you had access to the test would you use it?
OBJECTIVE: To assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis.
METHODS: We compared screening (day -14) and baseline (day 0) PASAT scores of 1009 patients from the FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial. We grouped patients into high and low learners if their PASAT score change was above or below the median change in their screening PASAT quartile group. We used Wilcoxon test to compare baseline disease characteristics between high and low learners, and multiple regression models to assess the respective impact of learning ability, baseline normalised brain volume and treatment on brain volume loss and 6-month confirmed disability progression over 2 years.
RESULTS: The mean PASAT score at screening was 45.38, increasing on average by 3.18 from day -14 to day 0. High learners were younger (p=0.003), had lower Expanded Disability Status Scale score (p=0.031), higher brain volume (p<0.001) and lower T2 lesion volume (p=0.009) at baseline. Learning status was not significantly associated with disability progression (HR=0.953, p=0.779), when adjusting for baseline normalised brain volume, screening PASAT score and treatment arm. However, the effect of fingolimod on disability progression was more pronounced in high learners (HR=0.396, p<0.001) than in low learners (HR=0.798, p=0.351; p for interaction=0.05). Brain volume loss at month 24 tended to be higher in low learners (0.17%, p=0.058), after adjusting for the same covariates.
CONCLUSIONS: Short-term practice effects on PASAT are related to brain volume, disease severity and age and have clinically meaningful prognostic implications. High learners benefited more from fingolimod treatment.
OBJECTIVE: To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing-remitting multiple sclerosis (RRMS).
METHODS: We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression.
RESULTS: Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R(2) = 0.48, p = 0.001) and on active MRI lesions (R(2) = 0.61, p < 0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R(2) = 0.75, p < 0.001), and both variables were retained as independently related to the treatment effect on disability progression.
INTERPRETATION: In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the 2 MRI measures predict the treatment effect on disability more closely when used in combination.
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.
Why don’t you support private prescribing and HSCT abroad?
The social media response to yesterday’s Barts-MS Hangout on HSCT has been rather mixed. A lot of commentators are being critical of us for creating too many hurdles regarding the access to HSCT and that we shouldn’t stop our patients going abroad for treatment. From my perspective, going abroad or to private units in the UK for HSCT is private healthcare at its worst. The countries who offer private HSCT, on a fee-for-service basis, are some of the countries with the largest health inequities in the world. These private HSCT units are in it for the money and hence are not that selective in whom they will treat. Can you pay? If you say yes, then you can be treated next week, but only after you put down a large deposit.
The founding principles of the NHS and other socialist healthcare systems are that healthcare is a basic human right, therefore it should be free at the point of access and it must be equitable. Private HSCT, private prescribing and even off-label prescribing undermine these principles and this worries me a lot. This is why I can’t and won’t openly support my patients travelling abroad for HSCT; you need to understand that when it comes to access to healthcare I am card-carrying socialist.
We at Barts-MS have been pushing our Essential Off-Label list to improve access to treatments in resource-poor environments. The problem with this is that adoption of off-label prescribing is patchy at best and creates pockets of prescribing in a desert of limited access. The latter creates massive variances in prescribing and inequity. This is why we decided a few years ago to hand the baton of promoting an Essential DMT List, including HSCT, which is on our list, to the MSIF (Multiple Sclerosis International Federation).
The MSIF is an umbrella organisation representing all of the MS Charities from across the world and is therefore in the best position to endorse and promote an Essential DMT list. The MSIF made the strategic decision to go via the WHO Essential Medicines List (WHO-EML). Over the last 2 years, we have actively been working on this and I have had the privilege of co-chairing the MSIF WHO-EML Taskforce with Professor Brenda Banwell. We managed to get an international consensus on three DMTs (glatiramer acetate, fingolimod and ocrelizumab) to be considered for the WHO-EML. Please note HSCT did not make the shortlist mainly because we are trying to address the unmet need in resource-poor countries. Our application is now online and we hope the wider MS community get behind our application. Our application is more than about these three DMTs, it is a political campaign to get the WHO and the world to realise that MS is a problem across the globe; MS is not just a rich world disease. For example, did you know that there are more people with MS in India than there are in the UK?
So to our critics out there, we at Barts-MS have a wider responsibility to the MS community and to support the NHS and the pwMS living in the UK by trying as best we can to uphold the founding principles of the NHS.
The live hangout will accessible via this link, or it can be viewed below. It will automatically be recorded to YouTube so you can watch it later if the time slot is unsuitable for you. If you watch on YouTube you will be able to ask questions using the YouTube chat function during the live recording.
Based on the early feedback we have produced a list of early questions that we will address. Please let us know if you have any other questions.
