We think that to ‘maximise brain health for the life of a person with MS (pwMS)’ we need to manage MS actively and holistically and promote brain-healthy behaviours. The ‘we’ here is not only HCPs but you and society, which includes regulators, politicians, educationalists, pharma, etc.
Another thing that people don’t get is that ‘life is a sexually-transmitted age-dependent neurodegenerative disease’ and that if we live long enough our nervous system fails. As MS reduces our reserve, by shredding axons, synapses and causing neuronal loss it brings age-dependent neurodegeneration forward.
Early ageing and MS worsening overlap and we face a big challenge separating progressive MS from premature ageing. This is why when people state that treatment X, for example, HSCT, halts progression they are exposing their naivety and lack of understanding of MS. HSCT is not anti-ageing and hence that component of MS worsening can’t be altered. In the case of HSCT, it may hasten the ageing process as some of the chemotherapy agents used as part of HSCT are neurotoxic.
HSCT supporters will typically point to the amazing EDSS data showing disease stabilisation and in some cases improvement. But MS is more than lower limb function and walking. What needs to be presented are multi-domain outcomes across multiple functional systems, in particular, cognition. MS is first and foremost a ‘preventable dementia’ and hence we need to monitor cognition over time and see what our treatments are doing to cognition.
The study below relates to ‘normal ageing’ but may be relevant to pwMS. It shows that playing analogue or board games reduces age-related cognitive decline. I suspect, based on the cognitive reserve hypothesis, these findings will apply to pwMS as well. Do you play board games? If you do you it may delay or slow down MS-related cognitive decline. Who would have thought of playing Monopoly as a potential DMT in MS?
Objectives: Playing analog games may be associated with better cognitive function but, to date, these studies have not had extensive longitudinal follow-up. Our goal was to examine the association between playing games and change in cognitive function from age 11 to age 70, and from age 70 to 79.
Method: Participants were 1,091 non-clinical, independent, community-dwelling individuals all born in 1936 and residing in Scotland. General cognitive function was assessed at ages 11 and 70, and hierarchical domains were assessed at ages 70, 73, 76, and 79 using a comprehensive cognitive battery of 14 tests. Games playing behaviors were assessed at ages 70 and 76. All models controlled for early life cognitive function, education, social class, sex, activity levels, and health issues. All analyses were preregistered.
Results: Higher frequency of playing games was associated with higher cognitive function at age 70, controlling for age 11 cognitive function, and the majority of this association could not be explained by control variables. Playing more games was also associated with less general cognitive decline from age 70 to age 79, and in particularly, less decline in memory ability. Increased games playing between 70 and 76 was associated with less decline in cognitive speed.
Discussion: Playing games were associated with less relative cognitive decline from age 11 to age 70, and less cognitive decline from age 70 to 79. Controlling for age 11 cognitive function and other confounders, these findings suggest that playing more games is linked to reduced lifetime decline in cognitive function.
For all the killjoys out there DMTs do work, i..e. they modify the course of MS and prevent you from reaching all disability milestones including the time to diagnosis of SPMS and EDSS 10.0 or death.
Please don’t listen to the zealots who are trying to spin fake news that the only treatment to prevent the development of progressive MS is HSCT; they are wrong. There are other options; the study below shows you can do it with currently licensed DMTs that are safer than HSCT. One message that is loud and clear with this data is that the earlier you treat the better and you have a much better outcome if you flip the pyramid and start on high-efficacy DMTs first-line.
IMPORTANCE: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.
OBJECTIVE: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.
DESIGN, SETTING, AND PARTICIPANTS: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years’ follow-up.
EXPOSURES: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).
MAIN OUTCOME AND MEASURE: Conversion to objectively defined secondary progressive MS.
RESULTS: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).
CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies’ risks, may help inform decisions about DMT selection.
I am beginning to think that immune reconstitution therapies or IRTs are ahead of their time. Many neurologists, people with MS (pwMS), payers – particularly fee-for-service insurance companies – and the regulators are unable to get their heads around how these agents work. In addition, a few recent review articles, written by colleagues, cast doubt on this treatment strategy and the terminology we use.
IRTs are the only treatments that are addressing the cause of MS and hence have the potential to cure MS. We will know in the near future how many pwMS in very long-term remission post -alemtuzumab, -HSCT or -cladribine are truly MS free. This information is critical to convince a sceptical field of the value of these treatments.
The mortality associated with HSCT makes people shudder. Although the risk of dying from one of the complications of HSCT is quoted as being between one of 1 in 333 (0.3%) to 1 in 50 (2%) many pwMS are taking this risk in the UK or abroad. Despite HSCT being a viable treatment option for pwMS in England and now Scotland many UK MSologists don’t routinely put this option on the table when discussing switching treatments with their patients who are failing other high-efficacy therapies. Why?
Even going to the easy-to-use, easy-to-monitor, oral cladribine option we are seeing slow adoption. Why? I am now convinced HCPs don’t understand IRTs, in particular, the concepts of frontloading of risk and long-term remission.
The study below shows that patients failing alemtuzumab in year one after the first course of five infusions, do very well after receiving their second course. Despite these patients having more active disease and early breakthrough activity, they do very well longterm with high chances of being rendered NEDA and experiencing disability improvement and having brain volume loss that slows markedly – into the normal range – after year 2.
DMTs are about protecting the end-organ or brain and keeping it as healthy as possible so that pwMS can live a normal life as possible and have the necessary reserve to deal with ageing when it sets in. Is this message difficulty to communicate? Knowing this brain volume data why wouldn’t we want to at least offer an IRT to all our patients with active disease and I mean first, second or third line? It is clear the sooner you are treated with an IRT the better you do.
I am now planning to do a series of online lectures on IRTs to explain why they should be so appealing as a treatment strategy for pwMS. Would you be interested in watching?
I also have a vested interest in getting IRTs adopted. We want to use them as induction agents in more advanced MS to be followed by maintenance therapies that target the processes within the brain and spinal cord to address smouldering MS.
BACKGROUND: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen.
OBJECTIVE: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers).
METHODS: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension.
RESULTS: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%).
CONCLUSION: Early relapsers’ outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit.
I post to manage expectations and counteract fake news.
There is a group of pro-HSCTers going around and saying HSCT is a cure for MS even in MSers with more advanced disease, i.e. it halts and reverses their disability. This is simply not correct and we have no published, peer-reviewed, data to support their position.
The meta-analysis below from Paulo Muraro and colleagues clearly shows that in MSers with SPMS and PPMS having HSCT the ‘majority of study subjects’ continue to progress. This is why most bone marrow transplant units generally don’t treat progressive MS. Even Richard Burt one of the main proponents of treating MS with HSCT stopped transplanting MSers with progressive MS when his BMT unit was still active.
The figure below from the Muraro paper confirms the above; over 60% of the SPMSers and 100% of the PPMSers worsened compared to about 45% of the RRMSers. Why? I suspect it is due to smouldering MS.
HSCT is simply a very potent IRT (immune reconstitution therapy) and is effective at switching off relapses and new focal MRI activity. We have no data to suggest that it impacts on smouldering MS. In fact, we have evidence to the contrary, that the chemotherapy used to deplete the immune system is neurotoxic and some patients actually develop worsening disability as a result of ‘chemo brain’ or acute neurotoxicity associated with the induction protocol. In the Canadian study, which uses myeloablative chemotherapy, treated patients lost more than 2% of their brain volume in year 1. Believe me, this is serious brain volume loss way above what you expect MS to do and is indicative of neurotoxicity. The reason why relapsing MSers cope with the HSCT conditioning is because of reserve and progressive MSers do not, because their MS has already consumed their reserve capacity.
Many years ago we showed that MSers undergoing BMT/HSCT release very high levels of neurofilaments as part of the induction protocol and the levels of neurofilaments released predicted worsening disability. In other words, the chemotherapy caused acute neurotoxicity and resulted in disability worsening. This is one of the reasons why the Rotterdam BMT unit, and many other units, stopped treating progressive MSers. However, if you go to a fee-for-service BMT unit they will treat all-comers. Why? It is called a business and money talks. Don’t be gullible.
What about the anecdotal cases of HSCT curing progressive MS? I can’t say I have seen a single case. All the patients in my practice with progressive MS who have gone abroad to have HSCT have continued to worsen on their return. I am aware of a case of a colleague of mine who had a patient who was in a wheelchair who had HSCT abroad who miraculously got up and walked after having HSCT. My colleague informed me that he had diagnosed this patient as having somatization disorder, a very common MS mimic, that is a psychiatric condition. I am, therefore, sceptical about miraculous anecdotes and I would urge you to be careful before you base your decisions to have HSCT based on anecdotes. What we as an MS community needs is published data on the risks and benefits of HSCT in advanced MS to base our decisions on.
IMPORTANCE: Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.
OBJECTIVE: To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.
DESIGN, SETTING, AND PARTICIPANTS: Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.
EXPOSURES: Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.
MAIN OUTCOMES AND MEASURES: The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.
RESULTS: Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).
CONCLUSIONS AND RELEVANCE: In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.
BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.
METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.
FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.
INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease’s aggressive nature.
OBJECTIVE: Chronic neurotoxicity is a recognized long-term complication following chemotherapy in a range of diseases. Neurotoxicity adversely affects patients’ quality of life. The objective of this study is to examine whether there is evidence of acute neurotoxicity.
METHODS: This prospective study included patients with secondary progressive multiple sclerosis (SPMS-BMT, n = 14) and hematological malignancies (HM-BMT, n = 17) receiving chemotherapy as preconditioning for bone marrow transplant. The control groups included SPMS patients matched for demographic and clinical data (SPMS-PL, n = 14) and healthy controls (n = 14). Neurodegeneration was assessed at baseline and longitudinally (months 1, 2, 3, 6, 9, 12, 24, and 36), combining a clinical scale for disability (Expanded Disability Status Scale [EDSS]), a serum protein biomarker for neurodegeneration (neurofilaments, NfH-SMI35), and brain atrophy measures (magnetic resonance imaging).
RESULTS: Disability progression was significantly more acute and severe following chemotherapy compared to placebo. Immediately after starting chemotherapy, serum NfH-SMI35 levels increased in 79% (p < 0.0001) of SPMS-BMT patients and 41% (p < 0.01) of HM-BMT patients compared to 0% of SPMS-PL patients or healthy controls. In SPMS-BMT serum NfH-SMI35 levels were > 100-fold higher 1 month after chemotherapy (29.73ng/ml) compared to baseline (0.28ng/ml, p < 0.0001). High serum NfH-SMI35 levels persisting for at least 3 months were associated with sustained disability progression on the EDSS (p < 0.05). Brain atrophy rates increased acutely in SPMS-BMT (-2.09) compared to SPMS-PL (-1.18, p < 0.05).
INTERPRETATION: Neurotoxicity is an unwanted acute side effect of aggressive chemotherapy.
If push came to shove would you really choose HSCT as a first-line treatment to treat your MS?
When asked on the blog yesterday which DMT would I choose if I had MS, I chose HSCT. One of my patients, who I have been looking after for over a decade, sent me an email stating how upset she was that I had never offered her HSCT. I clearly need to explain my position so as not to upset anyone else.
Firstly, HSCT is not on offer as a routine NHS therapy. At the moment HSCT is only considered as a 2nd or 3rd-line treatment in the most active patients. Another problem is that it is not on offer across the country. There are only a handful of MS centres that are prepared to refer their patients for HSCT. This means that access to HSCT is not equitable and explains why an increasing number of patients are having to travel abroad, at great personal cost, to receive this therapy. Inequity of care is against one of the founding principles of the NHS and is unacceptable.
The block in access to HSCT seems to be at the level of the neurologist/MSologist. NHS England guidelines for bone marrow transplant (BMT) units allows them to use up to 15% of their procedures to treat autoimmune conditions, which includes multiple sclerosis. As BMT units exist across the country access to these units would simply require a referral from a neurologist to the unit to perform HSCT on patients with MS. However, the latter is unlikely to happen unless the local MSologist champions HSCT as a procedure and gets their local haematology unit on board. It always takes a local champion to make things happen and our Barts-MS champion is Dr Ben Turner.
Another factor that has changed in the last 10 years is the strength of the evidence-base showing how effective HSCT really is as a treatment for MS. The most recent MIST trial, the first large randomised controlled trial, and several meta-analyses of HSCT, which have been extensively discussed on this blog, have confirmed that HSCT is a very effective therapy. At the same time the risks associated with HSCT have improved and the mortality in most BMT units is now below 1% for MS. This is now tipping the scales in favour of HSCT becoming a mainstream treatment for MS. There is however resistance from the MS community about HSCT been offered as a first-line therapy. Why? I suspect because the risk:benefit profile of HSCT has yet to be compared in a head-2-head study against our most effective licensed treatment. This why we are planning to do a head-2-head study of alemtuzumab vs. HSCT in the hope of generating this evidence. We know already that HSCT will be more cost-effective than alemtuzumab, but will it be more effective and as safe? Don’t try and second guess the results of this trial; I would not be surprised if there is no difference between these two treatments in terms of efficacy.
Please remember that most of the proponents of HSCT as a treatment for MS recognise that the major benefits from treatment will only be derived if HSCT is used early in the course of the disease. This explains why most BMT units don’t offer HSCT to pwMS with more advanced, or progressive, MS. However, this does not stop private, fee-for-service, units offering HSCT to all-comers. If you have the money and are willing to travel abroad you will be able to find a BMT unit that will treat you. I think this is wrong and will not happen in the NHS when HSCT eventually becomes widely available. We have to be honest with our patients about the risks and the benefits and why we will limit HSCT to those who benefit the most. In fact there is evidence that more advanced patients may actually be made worse by HSCT; the chemotherapy used to ablate the immune system is neurotoxic and may speed up neuronal loss. In addition, infections are common when you have HSCT and infections are well known to worsen MS disability in more advanced disease.
Please be aware that HSCT is not for the faint-hearted. It is a risky therapy with serious adverse events and quite a high mortality. Even a mortality rate of 0.3-0.5% is high when compared to other licensed DMTs. Should this stop us from offering HSCT first-line? I think not. If we are prepared to offer alemtuzumab, with its risk profile as a first-line treatment, why not HSCT? Most pwMS would agree that the decision regarding what is an acceptable risk to take should be taken by the patient and their families, and not the neurologist or other HCP. There is data showing that neurologists are much more risk-averse than pwMS. Neurologists need to acknowledge this bias, which is likely to be an unconscious bias, and let their patients make the decision.
What I am really trying to do by stating that if I had MS I would choose HSCT as my treatment is to reframe the DMT debate, particularly in relation to access to highly effective DMTs. By focusing on HSCT as a first-line treatment it should at least consider what your treatment objectives are in MS.
Framing is another a cognitive bias that was identified by Daniel Kahneman, the Nobel laureate, and his partner Amos Tversky. By moving the frame to the right, i.e to include HSCT as a 1st-line therapy, it makes it more likely for pwMS and their neurologists to choose more effective treatments. We now know that people who start on a low to moderate efficacy DMT do worse on average than those who start on a high or very high efficacy therapies do better. Despite this the majority of pwMS are not told this and are started on a low efficacy or platform DMTs without ever being given the option of a high efficacy DMT. Why? It is not due to lack of access to treatments as we now have several NICE and NHS England approved high efficacy DMTs available as first-line treatments.
So yes, if I had active MS I would want to have the full spectrum of high-efficacy DMTs available to choose from including HSCT. I would want to know about their relative efficacy and what the aim of the treatments are. I would certainly want to have a discussion about the possibility of a potential cure. Wouldn’t you?
By framing the spectrum of efficacy by having HSCT within the frame may nudge patients and their neurologists to move up the treatment ladder and choose a high efficacy DMT.
Unfortunately, HSCT as a first-line option is not going to happen any time soon, which is why I am trying to nudge the community to start debating the issue in earnest and why I want us to have a citizens jury on the issue.
A few weeks ago I did a post on using a Citizens Jury, as a potential way to deal with the emotive issue of a lack of access to HSCT as a potential 1st-line treatment for active MS in the UK.
A Citizens Jury can help sort out the disconnect between the needs or implied needs, of the MS community, and the position of the NHS and/or the HCPs in relation to HSCT. A Citizens’ jury 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 HCPs feel HSCT is too risky to be a mainstream treatment for MS, whereas a large and increasing number of pwMS don’t.
The following is the results of our survey. I hope the MS Society, NHS England, ABN (Association of British Neurologists) and other stakeholders reflect on these results and consider putting together a Citizens Jury to deal with this thorny issue.
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?
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.
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.
