Because cladribine and alemtuzumab are classified as immune reconstitution therapies (IRTs), and probably work in a similar way, they are tarnished with the same brush. However, cladribine’s immune depletion and reconstitution, and adverse event profile are very different to alemtuzumab’s and therefore cladribine should be considered on its own when weighing up the risks and benefits of treating highly-active MS during the COVID-19 pandemic. For example, the advice that pwMS need to shield after cladribine treatment is a very harsh call and in my opinion unnecessary. Why?
5. The effect of DMTS on the risk of SARS-CoV2 infection and COVID 19 disease remains uncertain and we commend pwMS and MS teams to continue to submit data to the UK MS Register study of COVID 19. We recommend that patients are counselled on the effect of a DMT on their individualised risk of COVID 19 disease, taking into account its duration of action; any comorbidities; and also the DMT’s impact on the efficacy of any future SARS-CoV2 vaccine. Patients should be informed if their treatment choice requires shielding [especially cladribine and alemtuzumab].
11. Cladribine should be started cautiously on a case-by-case basis when the risk of SARS-CoV2 is very high. Re-treatment should be delayed until the risk of infection is level 3 or below.
14. pwMS with mild symptoms of COVID-19 should not stop first-line DMTs, but infusions [and cladribine administration] should be delayed until symptoms resolve.
C. THE RISK OF COVID-19 IN PEOPLE WITH MS [PWMS] ON DISEASE MODIFYING THERAPIES [DMTS]
11. There is very limited experience4 of pwMS on cladribine becoming infected with SARS-CoV2 and the SmPC warns of herpetic viral infections being “common”. However, it may be considered on a case-by-case basis. When and where the rate of SARS-CoV2 infection is very high, the risks of increased infection for three months after cladribine administration, and the advice to shield, may outweigh its benefits.
D. DMTS IN PwMS WITH ACTIVE COVID 19 INFECTION
14. pwMS with mild symptoms of COVID-19 should not stop a first line DMT, but infusions [and cladribine administration] should be delayed until symptoms resolve.
We know that anti-SARS-CoV-2 immunity requires innate immune responses (neutrophils and macrophages) and T-cell responses (predominantly CD8+ responses) to clear the virus. Cladribine does not deplete monocytes and neutrophils and has a modest impact on CD8+ve T-cells. Therefore t is unlikely to have a major impact on anti-SARS-CoV-2 immunity.
On cladribine, T lymphocytes are in general depleted by about 40% and the vast majority of patients don’t drop their counts below 500/mm3. In the T-cell compartment, the CD8+ T-cells are much less affected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections and explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine treated subjects in the phase 3 trial programme.
In the phase 3 programme about a quarter of patients had a transient grade 3 or 4 lymphopaenia, but this tended to occur after the second course in year 2 in subjects who were redosed when their lymphocyte counts in year 1 had not yet recovered to above 800/mm3 (per-protocol dosing). We have used the trial data to model grade 3 and 4 lymphopaenia (<500/mm3), and estimate that less 7% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the cladribine redosing guidelines. This is important because most of the cases of zoster were in subjects who developed grade 3 or 4 lymphopaenia, which implies the risk of getting herpes zoster in real-life (post-marketing) is likely to be much lower than what we saw in the clinical trials.
Should we be so hung up about the lymphocyte count? When we explore the safety data of oral cladribine, from both the trial programme and post-marketing surveillance, we really don’t see a significant viral infection signal in cladribine-treated subjects. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. The following presentation is data that we recently presented at the AAN and EAN meetings and illustrates how uncommon viral infections are in pwMS treated with cladribine.
Based on these data I really don’t think it is necessary to for pwMS to shield during the current pandemic. All they need to do is maintain social distancing, practice good personal hygiene and avoid contact with potentially infectious people. This means that pwMS working in high-risk professions (healthcare and care sector workers with direct patient contact) who are treated with cladribine should not have direct patient-facing activities until they have recovered their lymphocyte counts to a safe level (>500/mm3 in people less than 60 years of age and >800/mm3 in those older than 60 years).
Although, cladribine is a remarkably good depleter of B-cells the B-cell numbers return quite quickly. The reconstituted B-cells are initially naive B-cells, which come from the bone marrow and are not memory B-cells. This is important for vaccine-readiness if a SARS-CoV-2 vaccine does emerge.
In comparison to cladribine, ocrelizumab and rituximab are given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over with time and the development of hypogammaglobulinaemia, which is not seen with cladribine. Once the immune system reconstitutes post-cladribine it can fight infections, immune survey the body for cancers and mount immune responses to new viral infections, such as SARS-CoV-2, and vaccines. In relation to vaccines both live and inactivated component vaccines can be given after cladribine.
The other important thing about cladribine is the monitoring requirements are low. Once you have had a course you only need a full blood count to be done 3 and 7 months after starting treatment. The rationale for this is that the 3-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts.
Another advantage of cladribine is that as a small molecule it penetrates the CNS; cerebrospinal fluid (CSF) levels are about 25% of what is found the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. I think this property of cladribine is very important and is one of the reasons why we are exploring cladribine as a treatment for progressive MS in the CHARIOT-MS trial.
I think cladribine is a very misunderstood DMT and has been hard done by in the COVID-19 treatment guidelines which in general are not evidence-based nor are they necessarily based on basic immunological principles.
As the COVID-19 pandemic is likely to have a long tail with a vaccine 18 to 24 months away I think we the MS community should reconsider our position on oral cladribine as cladribine addresses many of the issues of treating highly active MS in these troubling times and it has the added advantage of leaving people with MS with a reconstituted vaccine-ready immune system if and when a SARS-CoV-2 vaccine arrives.
Please note that I am not saying cladribine is safe; no DMT is safe. However, cladribine has a very well-defined risk-benefit profile that is less risky than what is been suggested in the ABN guidelines. The risk-benefit profile of cladribine simply allows you to counsel patients with highly-active MS about their treatment options during the COVID-19 pandemic and cladribine deserves to be part of that discussion.
CoI: multiple, but in particular I was the principal investigator on the oral cladribine phase 3 trial and have been involved with the development of oral cladribine as a treatment for MS since 2002.
This post explains why I have started to refer to cladribine as a small molecule anti-CD20/CD19 therapy and why oral cladribine should be part of the exit strategy to treat MS during the tail of the COVID-19 pandemic.
Although we use cladribine as an immune reconstitution therapy and often compare it to alemtuzumab it is, in fact, closer to anti-CD20 therapies in terms of its immunodepletion profile. This distinction is particularly important during the COVID-19 pandemic because it has allowed us to classify cladribine in an intermediate risk DMT, which allows us to treat MS with an IRT when we can’t use alemtuzumab.
Cladribine’s pros:
Cladribine is an oral therapy; hence no visits to COVID-HOT hospitals or institutions.
It kills cells gradually by a process called apoptosis. Cells dying from apoptosis are phagocytosed or swallowed by macrophages and as a result, there is no cell lysis or bursting open of the cells and the release of their contents that causes a cytokine release syndrome. This means there is no need to pre-treat patients with steroids, which we are trying to avoid at present.
Cladribine does not deplete monocytes and neutrophils and has a moderate impact on so-called NK cells. As the innate immune system is left intact there is a low risk of bacterial and other infections during the depletion phase and the innate cells can help fight viral infections, such as SARS-CoV-2.
T lymphocytes are in general depleted by about 40%-50% and most patients don’t drop their counts below 500/mm3. In the phase 3 programme about a quarter of patients had a grade 3 or 4 lymphopaenia, but this tended to occur after the second course in year 2 in subjects who were redosed when their lymphocyte counts had not recovered to above 800/mm3. We have used the trial data to model grade 3 and 4 lymphopaenia. I.e. less than 500/mm3, and estimate that less 5% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the redosing guidelines. This is very important as lymphopaenia is probably the most important risk factor for viral and severe viral infections.
In the T-cell compartment, the CD8+ T-cells were less effected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections. This probably explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine treated subjects in the phase 3 trial programme. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. In fact, the infection profile on cladribine, including the zoster signal, was much more similar to that which we see with ocrelizumab compared to alemtuzumab.
Cladribine is a remarkably good depleter of B-cells. B-cells number drop quicker than T-cells numbers; i.e. within days to weeks. In addition, B-cells are depleted by about 90% and importantly memory B-cells are severely depleted and to a similar level that we see with alemtuzumab. Importantly, when the B-cell numbers return these are so-called naive B-cells, which come from the bone marrow and are not memory B-cells. Interestingly, when you stop an anti-CD20 therapy such as ocrelizumab or rituximab and allow B-cell reconstitution they are also naive and are not memory B-cells that return in the short-term. In other words cladribine, alemtuzumab and ocrelizumab have similar effects on B-cells.
Please note that because ocrelizumab and rituximab are given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over with time and the development of hypogammaglobulinaemia. This is not seen with cladribine. Once the immune system reconstitutes post-cladribine it can fight infections, immune survey the body for cancers and mount immune responses to new viral infections, such as SARS-CoV-2, and vaccines. In relation to vaccines both live and inactivated component vaccines can be given after cladribine.
The other important thing about cladribine is the monitoring requirements are low. Once you have had a course you only need a full blood count to be done 3 and 7 months after starting treatment. The rationale for this is that the 3-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts. What this means during the COVID-19 pandemic is that if you are treated with oral cladribine and at 3 months your lymphocyte counts is above 500/mm3, which will be the vast majority of treated patients, you don’t need to self-isolate. In the 3-4% who have a lymphocyte count below 500/mm3 at month three, you will need to continue to self-isolate until your counts go above 500/mm3. To find out the latter you could wait another three months for the next blood test our you could ask your GP or MS team for an earlier test.
When you look at how cladribine works, i.e. it needs to be activated by an enzyme call DCK (deoxycytidine kinase) and broken down by an enzyme called ADA (adenosine deaminase), the profile of cells expressing the correct ratio of these enzymes matches the B-cell population that expresses CD19 and CD20 and explains why B-cells are more susceptible to the effects of cladribine than T-cells.
Another advantage of cladribine is that as a small molecule it penetrates the CNS. Cerebrospinal fluid (CSF) levels are about 25% of what is found the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. I think this property of cladribine is very important and is one of the reasons why we are exploring cladribine as a treatment for progressive MS in the CHARIOT-MS trial.
In a similar way to ocrelizumab, I think cladribine has been hard done by COVID-19 guidelines that have stated not starting or not redosing cladribine during the COVID-19 pandemic. Why? Where is the science to support this position?
Now that we can see the pandemic is not going to end anytime soon and with a vaccine 18 or 24 months away I think we should reconsider using oral cladribine as it addresses many of the issues of treating highly active MS in these troubling times and it has the added advantage of leaving people with MS with a reconstituted vaccine-ready immune system if and when a SARS-CoV-2 vaccine arrives.
Please note that I am not saying cladribine and/or anti-CD20 therapies are safe. They have well-defined risk-benefit profiles that are less risky than what has been proposed by many people in terms of developing severe COVID-19. These risk-benefit profiles simply allow you to counsel patients with active MS about their treatment options during the COVID-19 pandemic.
I personally think both anti-CD20 therapies and cladribine are two highly effective therapies that allow a treatment exit strategy during the long tail of the SARS-CoV-2 pandemic.
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.
What do you do when you get recurrent disease activity on cladribine?
I am repeatedly being asked what to do about disease activity in patients treated with cladribine. The following is my suggestions on how to approach this thorny issue.
As you know disease activity on immune reconstitution therapies (IRTs) don’t necessarily mean you failed or are failing the therapy. Disease activity could be an indication to retreat with an additional course. Interpreting when and what to do depends on when the disease activity emerges and how severe it is.
Post-course 1
If you have a relapse after the first course (cycles 1 & 2) of cladribine I would hold fast and have the second course. There is no reason why someone who has disease activity in year 1 post-cladribine won’t necessarily respond to the second course. There is, however, one proviso here. With alemtuzumab, another IRT, rare patients get rebound activity, over and above baseline activity, around months 7-9 post the first course of alemtuzumab infusions. Why this happens we don’t know. We have not observed this with cladribine yet, but it could theoretically happen. In this situation, the disease activity is so severe that most of these patients are offered alternative treatments, in particular, anti-CD20 therapies (rituximab or ocrelizumab), mitoxantrone, cyclophosphamide or HSCT.
When we see recurrent disease activity in year 1 post-alemtuzumab we have often brought forward the second course of alemtuzumab. I see no reason why we wouldn’t consider this with cladribine as well, provided the total lymphocyte counts have recovered to above 800/mm3.
Post-course 2 – year 2
If disease activity occurs in year 2 this is not good news. This would indicate that the patient has not responded to cladribine and would be an indication to switch therapeutic strategies.
Post-course 2 – year 3 & 4
If you have disease activity in years 3 & 4 the timeframe covered by the current cladribine label you are not meant to retreat with cladribine. However, this makes no sense to me. IRT works by depletion and reconstitution. In some people, the two cycles of depletion with cladribine may not be sufficient to deplete the autoreactive pool and hence MS disease activity resurfaces. I personally think there is no reason why a further course of cladribine should not be offered alongside other DMTs in this situation. This is exactly how we use alemtuzumab in this situation; the difference being alemtuzumab is now licensed to be used in this way. Clearly there is an evidence gap around cladribine and hopefully, this will be filled as real-life data sets emerge in the future.
Post-course 2 – after 4years
Similar to the above I see no reason why a further course of cladribine should not be offered alongside other DMTs in this situation. This is how we use alemtuzumab and other IRTs. I am aware of one patient in the US has had 7 courses of intravenous cladribine over a period of 21 years.
The future
Cladribine has a variable treatment effect on the total lymphocyte counts. There are biochemical reasons why this may occur. I see in the future adapting the dose of cladribine we use to achieve an optimal level of lymphocyte depletion. This makes sense.
I also see cladribine being used as induction therapy, i.e. after an initial course of cladribine, we will be following it with maintenance therapy. Based on the memory B-cell hypothesis BTKi (Bruton’s Tyrosine Kinase inhibitor) or teriflunomide (antiproliferative/antiviral) makes the most sense at present.
I would love to do a trial of an IRT followed by maintenance therapy. Any takers? Any funders? In terms of safety and cost, I would go off-label and test rituximab followed by leflunomide vs. rituximab as an IRT.
The following is a visual summary of some of the information above.
I was still wet behind the ears, in my 3-year as a neurology registrar in Johannesburg, when I first used an off-label DMT in MS.
I manage to convince Vivian Fritz, my professor of neurology, to allow us to treat one of her patients with MS with mitoxantrone. This was shortly after the first case series had emerged from Germany.
The patient concerned was a young woman with malignant MS who had one relapse after another and was in our ward for steroids and neurorehabilitation. She had just had a severe spinal cord relapse. She had an EDSS of 8.5 (bed bound with partial loss of hand and arm function). She had had MS for just 2 years. I proposed that she would likely die from her MS if we did nothing to stop her attacks. What had she, and her family, to lose by trying a course of mitoxantrone?
Viv Fritz listened and read the case series. After some reflection, she finally agreed to us trying mitoxantrone in her patient. We went ahead with a course of infusions as per the case series. The patient did so-so; i.e. we managed to stop her having more attacks, but she never got out of a wheelchair. I heard later that she sadly died about 2 years later after she developed septicaemia from an infected pressure sore.
The point I am making about this case is that as a neurology trainee in South Africa I was able to read about a potential innovation in Europe, suggest it to my Professor, argue the case and change our unit’s practice. There were other examples of OLP in SA; it was common in Johannesburg and I suspect it is still happening.
In comparison, OLP is not universal. I have just returned from a short visit to Japan where I found the culture amongst Japanese neurologists to be very similar to parts of the UK in relation to OLP. Very few Japanese neurologists are prepared to stick their heads above the parapet and prescribe off-label DMTs. Why? And what are the potential consequences of not adopting OLP for their patients?
With regards to why I think it is cultural. OLP seems to be more common in cultures that allow individuals to express themselves and challenge the status quo. Japanese neurologists are very deferential and respect their superiors. The same applies to trainees in the UK. For OLP to be widely adopted in Japan and the UK, heads of department, or the ‘neurology establishment’, will have to lead the way.
I am personally in favour of OLP as an engine of innovation. So many of our DMTs in MS have been developed from the insights and actions of individual neurologists who were brave enough, yes brave enough, to give it a go. Larry Jacobs administered intrathecal interferon-beta to his patients based on the hypothesis that MS was due to a virus. Interferons are foremost antiviral agents hence their name. Professor Jacobs saw positive results in a few of his patients and the rest is history. Interestingly, we still don’t know exactly how interferon-beta works. It may be working in MS as an antiviral agent; we just don’t know. Nobody to my mind has disproved the antiviral hypothesis of interferon-beta’s mode of action.
Professor Larry Jacobs; interferon-beta pioneer
Mauch and colleagues tried mitoxantrone, an anti-proliferative chemotherapy agent, on the basis that MS is an autoimmune disease. Mitoxantrone is cell depleting chemotherapy agent and was the first immune reconstitution therapy (IRT) to be licensed. The idea is to simply kill the autoimmune cells responsible for causing MS. It took more than a decade of wider adoption of off-label mitoxantrone prescribing and research before mitoxantrone was eventually licensed as a treatment for MS.
Cyclophosphamide was less fortunate. Cyclophosphamide had been tried in MS for similar reasons as mitoxantrone. Unfortunately, cyclophosphamide was trialled in an era when the MS community didn’t know how to do trials. Cyclophosphamide failed as it was tested in more advanced MS and all the trials were underpowered, i.e. the trials had too few patients to be definitive. I am prepared to bet that if cyclophosphamide was formally tested in early in MS and the trials were adequately powered that it would be shown to a highly-effective DMT.
A more well-known example of OLP and innovation is Professor Alastair Compston’s off-label use of alemtuzumab. It started with Prof. Compston using it in a handful of patients in the early 1990s. Alemtuzumab was being tried in MS based on the same hypothesis as that for mitoxantrone and cyclophosphamide, i.e. MS is autoimmune and that to treat it and potentially cure MS you need to reboot the immune system killing off the autoimmune cells or at least regulating them when the immune system reconstituted itself.
I recall attending my first meeting in Cambridge, in late 1993 shortly after arriving in the UK to do my PhD, when Alastair presented the results of his first two patients. At the end of the meeting Professor Newsome-Davis, a senior and well-respected neuroimmunologist said to me that he didn’t agree with this approach. I recall him saying what we really needed was a pair of molecular tweezers and not a sledgehammer to treat autoimmunity. Unfortunately, the molecular tweezers are still the holy grail and without Alastair Compston’s perseverance, alemtuzumab would have never made it to the clinic.
Another example, is Prof. Jonathan Edwards, a rheumatologist at UCLH, who was brave enough to successfully try rituximab as a potential treatment for rheumatoid arthritis (RA). This was a very counterintuitive as the whole world at the time thought RA was a T-cell mediated autoimmune disease. The success of rituximab in RA led to senior executives at Genentech drawing up a list of other autoimmune diseases to try rituximab in. This and other factors subsequently led to Anne Cross trying rituximab in MS. Without a brave clinician trying OLP of an anti-CD20 in RA, we wouldn’t have ocrelizumab and several other me-too anti-CD20s in trials for treating MS.
There are similar stories for dimethyl fumarate, daclizumab, cladribine and some of the other emerging DMTs. Innovation in MS and other areas of healthcare emerge in an environment where OLP is championed and clinicians and their patients are brave enough to test the waters. What has changed?
It seems as if Barts-MS is being criticised, by some UK neurologists, for our compassionate use of off-label subcutaneous cladribine in more advanced MS. I don’t understand this as our position is no different from that of our predecessors mentioned above. We are simply building on a hypothesis that inflammation drives MS disease progression at all stages of the disease. We don’t agree with the 2-staged disease hypothesis of MS, i.e. that MS has an inflammatory phase that is followed by a neurodegenerative phase. The data overwhelming supports the parallel hypothesis that inflammation drives neurodegeneration throughout the course of the disease.
The implications of the parallel hypothesis of MS is that MS is potentially modifiable by anti-inflammatory therapies throughout its course; this even applies to advanced MS, which is why we will be formally testing DMTs in people who are already using wheelchairs for their mobility.
Another implication of the parallel hypothesis of MS, i.e. MS is always both inflammatory and neurodegenerative, is that we need to build a sandwich with an anti-inflammatory therapy, or a combination of anti-inflammatory therapies, at the base and to then use this as a platform on which to build the layers of the sandwich, which includes add-on neuroprotective, remyelination and neuro-restorative therapies.
At the same time we need a holistic approach and to focus on all the other factors that may impact on the health of the brain of someone with MS. This is why we need to proactively manage all of the things that are potentially associated with accelerated ageing in pwMS.
For this reason, I have been proposing for some time that we adopt the marginal gains paradigm when treating MS. Dave Brailsford from the British cycling team is acknowledged as making the marginal gains approach mainstream.
“The whole principle came from the idea that if you broke down everything you could think of that goes into riding a bike, and then improved it by 1%, you will get a significant increase when you put them all together.” Sir Dave Brailsford.
Small changes in many things can have a massive impact on the overall outcome. Prior to Dave Brailsford taking over as head coach of the UK cycling the team, it was in the doldrums. In 1996, prior to adopting the marginal gains philosophy, Team GB was in 12th place in the Olympic Games medal table with two bronze cycling medals. In comparison at the Beijing games in 2008 Team GB won 12 medals from 10 events; 7 gold, 3 silver and 2 bronze medals.
Why can’t we apply marginal gains to the management of MS? If you have MS, you need to ask what you need to do across your disease course to maximise your chances of having a good outcome. This means not only focusing on optimising your MS DMTs but doing all the lifestyle things you can do and more.
For the naysayers, who are criticising Barts-MS for trying to treat people with advanced MS (wheelchair users) and/or active secondary and primary progressive MS, can you imagine what it is like to be told that ‘you are beyond hope and there is no treatment that can help you’? Or ‘there is nothing I can do you for you as you have progressive MS’? This is why it is important to learn how to spread hope and to try and improve everything you possibly can for your patients with MS.
Spreading the hope is why we are doing the #CHARIOT-MS and #ORATORIO-HAND studies, why we are planning the #SALVAGE-MS study and trying to optimise our MS service, within the confines of the NHS, to adopt a marginal gains approach to managing MS.
I would also like to remind the naysayers that they seem not to have noticed that progressive MS is now modifiable? Ocrelizumab is licensed for active PPMS and Siponimod is licensed for active SPMS in the US and is likely to get an SPMS label in Europe. In addition, there are several other progressive trials underway with a high likelihood of being positive. We are now in an era where progressive MS is treatable.
If you are a naysayer, can I suggest you take off your blinkers, buy a pair of rose-tinted spectacles and smell the roses? Our compassionate use of off-label cladribine has allowed us to collect enough observational data to make the case for doing a trial of cladribine in more advanced MS. We would not have been able to get this point without OLP. For this, we would like to thank our patients and some of our colleagues for their ongoing support and to put DrK on a pedestal for his perseverance and resilience.
We won’t let the critics silence us and distract us from the job at hand; preventing MS (#PreventMS), treating MS early and effectively (#AttackMS, #ThinkCognition) and treating MS in the more advanced stages (#Proximus, #ThinkHand, #Over&Under, #ChariotMS, #OratorioHand, #SalvageMS).
As I write this post I wonder what our colleagues are going to say about our strategy of targeting the intrathecal plasma cell response with an add-on off-label therapy that is currently licensed to treat myeloma (#SIZOMUS)? I suspect the same naysayers will continue to advise their patients to stay away from our centre. At Barts-MS we are proud to practice experimental medicine. Without brave and bold scientists & clinicians and their patients, who are prepared to volunteer for clinical trials using off-label therapies, the innovation cycle, at least in the UK, will grind to halt.
Disclaimer: Please note that off-label prescribing is not a substitute for on-label prescribing unless it is the only way for people living with MS to access DMTs in resource-poor environments.
Jacobs et al. Intrathecal interferon reduces exacerbations of multiple sclerosis. Science. 1981 Nov 27;214(4524):1026-8. Ten patients with multiple sclerosis who were treated with human fibroblast interferon (IFN-B) for 6 months showed a significant reduction in their exacerbation rates compared with their rates before treatment (P < .01). The IFN-B was administered intrathecally by serial lumbar punctures. There was no significant change in the exacerbation rates of ten multiple sclerosis control patients before and during the period of observation. The IFN-B recipients have now been on the study a mean of 1.5 years, the controls, 1.2 years. The clinical condition of five of the IFN-B recipients and one of the control patients has improved, whereas the condition of five of the controls and one of the IFN-B recipients has deteriorated (P < .036). These findings warrant cautious optimism about the efficacy of intrathecal IFN-B in altering the course of multiple sclerosis and support concepts of a viral or dysimmune etiology of the disease.
Mauch et al. Treatment of multiple sclerosis with mitoxantrone. Eur Arch Psychiatry Clin Neurosci. 1992;242(2-3):96-102. Ten multiple sclerosis patients, all with a rapid deteriorating disease profile, were treated with 12 mg/m2 of the cytostatic agent mitoxantrone, administered every 3 months. This dosage is only 25% of what a patient with a solid tumour would normally receive during the same time period. In all treated patients the deterioration was stopped following the initial dosage; in four out of ten patients there was even an immediate improvement of the neurological status. Eight out of nine patients showed an improvement after 1 year as compared with their enrollment status; the other one remained stabile. In correlation with the clinical improvement, the mean P100 latencies of visual evoked potentials showed a reduction after 1 year. However, the changes identified through magnetic resonance imaging were even clearer than those seen clinically. At admission, this group of patients presented with a total of 169 gadolinium (Gd)-enhancing lesions. Only 10 lesions were enhancing in nine patients 12 months after the initiation of treatment. It appears that mitoxantrone accelerates the disappearance of Gd-enhancing lesions and prevents the development of new ones. Minimal side effects such as mild nausea and a slight faintness were evident in six patients and then for only 1-2 days.
Moreau et al. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 1994 Jul 30;344(8918):298-301. The central nervous system lesions of multiple sclerosis (MS) can be detected by magnetic resonance imaging (MRI) and the initial perivascular inflammatory component is distinguished by the presence of gadolinium enhancement. To assess the effect of systemic lymphocyte depletion on disease activity, seven patients with MS received a 10-day intravenous course of the humanised monoclonal antibody CAMPATH-1H (anti-CDw52). With some variations in the protocol, enhanced cerebral MR images were obtained monthly for 3-4 months before and at least 6 months after treatment. 28 enhancing areas were detected on the first series of 7 scans; 51 additional active lesions were identified on 18 scans before treatment; 15 were detected on 20 scans done over the next 3 months, but only 2 active lesions were seen on 23 scans during follow-up beyond 3 months. The difference in lesion incidence rate before and after treatment varied and the rate ratio was significantly reduced in only three patients. Collectively, in a “meta-analysis”, the rate ratios were 0.15 [corrected] (95% CI 0.09-0.24) for all seven patients and 0.24 (0.14-0.42; p < 0.001) with exclusion of the patient whose scanning schedule differed. The effect of CAMPATH-1H on disease activity provides direct, but preliminary, evidence that disease activity in MS depends on the availability of circulating lymphocytes and can be prevented by lymphocyte depletion. It is too early to say anything about the clinical results of treatment with this agent.
Edwards et al. B-lymphocyte depletion therapy in rheumatoid arthritis and other autoimmune disorders. Biochem Soc Trans. 2002 Aug;30(4):824-8. B-lymphocyte depletion therapy is being explored in a wide range of autoimmune disorders. In many, there is early evidence for efficacy, and immunosuppression has not been a major problem. The mechanism of action is unclear but appears to be consistent with the lowering of autoantibody levels, where relevant antibodies are quantifiable. An interesting finding is the persistence of clinical improvement for periods of 1 year or more after B-lymphocyte return, which supports the concept that stochastic generation of rare pathogenic B-lymphocyte subsets may be a rate-limiting step in pathogenesis.
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.
Is targeting the B-cell sufficient to get on top of MS or do we need something extra?
I spoke at the MS Nurses’ MS@TheLimits2019 meeting at the Royal College of Physicians yesterday. My brief was to cover the role of B-cells in the pathogenesis of MS and to review the converging evidence that supports B-cells being the central player in the pathogenesis of MS.
It is clear that depleting B-cell therapies are very effective in controlling relapses and MRI activity. With a very favourable safety profile and relatively low treatment and monitoring burden, B cell therapies are likely to become one of the most widely prescribed classes of DMT. However, B-cell therapies don’t match HSCT, alemtuzumab and natalizumab when it comes to downstream end-organ damage markers, in particular, brain volume loss. Why? I wish I knew. But if I knew the answer to this question I would have a pretty good idea about the cause of MS.
A clue may be in the ‘Field Hypothesis‘. It is clear to me that relapses and focal MRI activity are not the primary events in MS. Focal inflammation is not MS. Focal inflammation is in response to what is causing MS and the cause is likely to be something in the CNS. Focal changes occur in the white matter weeks to months before you get a Gd-enhancing lesion. When you stop natalizumab and allow re-trafficking of lymphocytes you get rebound disease activity way and above what one would expect from pre-treatment baseline levels of disease activity. What is happening in the brain, or field, of these patients to trigger such a vigorous inflammatory response? Could it be a virus? Importantly, B-cells appear to be needed for the rebound response. Rituximab, and I suspect ocrelizumab, are very effective in preventing rebound. However, as both these agents target a small subset of T-cells you can’t claim categorically that the rebound is only driven by B-cells.
The difference between HSCT, alemtuzumab and natalizumab and the anti-B cell therapies (rituximab, ocrelizumab and possibly cladribine) is the former take out or inhibit trafficking of both T & B cells. As HSCT and Alemtuzumab have the best data in relation to long-term remission, or potential cures, you have to conclude that you need to target both B cell and T cells (substantial peripheral depletion) if this is your treatment aim.
Please note that I classify cladribine as a B-cell depelter and not a dual B and T cell depelter. The level of T-cell depletion with cladribine is modest at the licensed dose (~50%) which is not sufficient to put it into the same class as alemtuzumab and HSCT. This is one of the reasons why I refer to cladribine as being a SIRT (selective immune reconstitution therapy) and the others as NIRTs (non-selective immune reconstitution therapies).
I have always made the point that to treat MS you need much more than an anti-inflammatory and that you also have to have neuroprotective therapies and potentially remyelinating agents on board as well. If you have disabilities we need to be thinking about neurorestorative therapies and finally you need to target lifestyle and wellness to tackle the issue of comorbidities and ageing.
So in short, targeting B-cells is important, but not sufficient to get on top of the shredder.
You will see that a large part of my talk was covering the link between EBV, B–cells and MS. The B-cell hypothesis at least strengthens the case for EBV being the cause of MS and the need for an EBV vaccine for MS prevention trials. Please don’t forget that EBV lives inside memory B cells and hijacks the B cell’s biology in many ways that have potential relevance to MS and other autoimmune diseases.
My talk will be available online in a few weeks to help you interpret my presentation. In the interim you can download my talk from my slide sharing site.
