How do we know if someone is cured of having MS?
I hope you understand that this definition of a cure is incompatible with the terms ‘repair’ and ‘regeneration’. The latter are separate processes that are independent of a so-called biological cure. We clearly need repair and regeneration agents to treat pwMS who have accumulated a significant amount of damage to their nervous systems. In comparison, in pwMS who have been cured of their MS and have not had any significant damage will not need to undergo treatments to repair and/or regenerate their nervous systems.
Based on our current understanding a cure can only really occur in relation to IRTs (immune reconstitution therapies; e.g. alemtuzumab, cladribine & HSCT), i.e. treatments that are given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity tends to return and in some cases, particularly with anti-trafficking agents (natalizumab and fingolimod), to a greater extent than before.
Let’s say we have treated a group of pwMS early in the course of their disease with an IRT and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 10, 15, 20 or 25 years? In the past, we have proposed defining a cure as NEDA at 15 years post-treatment as a starting point (see MSARD Editorial below). Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that should be accepted by the wider community; this may be wishful thinking many in the field are saying that we can’t cure MS, therefore, we should not be having this discussion.
In addition, the average time to the onset of secondary progressive MS is ~14-15 years so one would expect to see a significant proportion of people manifesting with SPMS in this timeframe. If we had got the autoimmune hypothesis wrong and the IRTs don’t work then I would estimate at least a third should have SPMS at 15 years if our hypothesis is wrong. The problem with 15 years is that it is a long to wait if you have MS. Many pwMS want to know ‘now’ if an IRT offers a cure, therefore we need data to convince the naysayers to support the ‘cure hypothesis’. Hopefully, convincing data will change their minds and get them to at least offer IRTs to more of their patients.
Deep phenotyping: In the past, I have proposed a deep phenotyping project to look at pwMS who are NEDA-2 post-IRT to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. I proposed interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term that refers to the interrogation of the CNS to see if the IRT has stopped ongoing damage and protected reserve capacity.
The study that has come closest to reaching this 15-year time point is the Canadian myeloablative HSCT cohort (see below). Mark Freedman, the principal investigator, has told me that all of these patients remain NEDA-2 (no relapses or MRI activity) although some have worsened in relation to their disability, which may be a result of previous damage and not ongoing MS disease activity. However, the most impressive observation is that this cohort of patients, who all have highly active MS prior to HSCT, has ‘normalised’ their rate of brain volume loss or atrophy after an initial precipitous drop in brain volume due to pseudoatrophy and/or chemotherapy-induced neurotoxicity. Mark Freedman has also said that about a third of these patients, who have had lumbar punctures, have lost their OCBs (personal communication). However, the spinal fluid analyses have all be done quite early on hence we don’t know how many subjects who have reached 10 years of follow-up or more have persistent OCBs. Wouldn’t this be an interesting fact to know?
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 GdGd-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.
This is a very difficult question that I keep getting asked.
How will we know if we have cured MS?
Based on what I have said in my recent post ‘Explaining why you get worse despite being NEDA‘ you may be cured of our MS, but still, have progressive disease. The difference between progressive disease, which is due to previous MS damage and that which is due to premature ageing is that the former should burn-out, i.e. after a period of time, your worsening disability should eventually stop or flat-line. In comparison, premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier would be a much easier task.
I hope you understand that this definition of a cure is incompatible with the terms ‘repair’ and ‘regeneration’. The latter are separate processes that are independent of a so-called biological cure. We clearly need repair and regeneration agents to treat pwMS who have accumulated a significant amount of damage to their nervous systems. In comparison, in pwMS who have been cured of their MS and have not had any significant damage will not need to undergo treatments to repair and/or regenerate their nervous systems.
Based on our current understanding a cure can only really occur in relation to IRTs (immune reconstitution therapies; e.g. alemtuzumab, cladribine & HSCT), i.e. treatments that are given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity tends to return and in some cases, particularly with anti-trafficking agents (natalizumab and fingolimod), to a greater extent than before.
Let’s say we have treated a group of pwMS early in the course of their disease with an IRT and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 10, 15, 20 or 25 years? In the past, we have proposed defining a cure as NEDA at 15 years post-treatment as a starting point (see MSARD Editorial below). Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that should be accepted by the wider community; this may be wishful thinking many in the field are saying that we can’t cure MS, therefore, we should not be having this discussion.
In addition, the average time to the onset of secondary progressive MS is ~14-15 years so one would expect to see a significant proportion of people manifesting with SPMS in this timeframe. If we had got the autoimmune hypothesis wrong and the IRTs don’t work then I would estimate at least a third should have SPMS at 15 years if our hypothesis is wrong. The problem with 15 years is that it is a long to wait if you have MS. Many pwMS want to know ‘now’ if an IRT offers a cure, therefore we need data to convince the naysayers to support the ‘cure hypothesis’. Hopefully, convincing data will change their minds and get them to at least offer IRTs to more of their patients.
Deep phenotyping: In the past, I have proposed a deep phenotyping project to look at pwMS who are NEDA-2 post-IRT to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. I proposed interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term that refers to the interrogation of the CNS to see if the IRT has stopped ongoing damage and protected reserve capacity.
The study that has come closest to reaching this 15-year time point is the Canadian myeloablative HSCT cohort (see below). Mark Freedman, the principal investigator, has told me that all of these patients remain NEDA-2 (no relapses or MRI activity) although some have worsened in relation to their disability, which may be a result of previous damage and not ongoing MS disease activity. However, the most impressive observation is that this cohort of patients, who all have highly active MS prior to HSCT, has ‘normalised’ their rate of brain volume loss or atrophy after an initial precipitous drop in brain volume due to pseudoatrophy and/or chemotherapy-induced neurotoxicity. Mark Freedman has also said that about a third of these patients, who have had lumbar punctures, have lost their OCBs (personal communication). However, the spinal fluid analyses have all be done quite early on hence we don’t know how many subjects who have reached 10 years of follow-up or more have persistent OCBs. Wouldn’t this be an interesting fact to know?
So yes, ‘if all you want for Christmas is an MS cure’ it may be staring you in the face.
Banwell et al. Editors’ welcome and a working definition for a multiple sclerosis cure. Multiple Sclerosis and Related Disorders. 2013; 2(2):65-67.
…. Defining a cure in MS is a difficult task. How long should we wait before declaring a victory; 15, 20 or 25 years? Oncologists have back-tracked on this issue and instead of a cure they now prefer to use the term NEDD, or no evidence of detectable disease, at a specific time-point knowing full well that a limited number of subjects will relapse and present with recurrent disease after this point. We propose using the term NEDA, or no evident disease-activity, at 15 years as a starting point for defining a cure. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a usual endpoint. In addition, the median time to the onset of secondary progressive MS is ~10-11 years (Kremenchutzky, Rice et al. 2006) and is well within the 15-year time window of our proposed definition of a cure. At present NEDA is defined using a composite of a) no relapses, or b) no EDSS progression, or c) no MRI activity (new or enlarging T2 lesions or no Gd-enhancing lesions) (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). This description is currently based on data that is routinely collected in contemporary clinical trials (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). The definition of NEDA will evolve with technological innovations and clinical practice, and in the future, it will almost certainly include MSer-related outcomes, grey matter disease activity, an index of brain atrophy and hopefully a CSF biomarker profile…..
References:
…. Defining a cure in MS is a difficult task. How long should we wait before declaring a victory; 15, 20 or 25 years? Oncologists have back-tracked on this issue and instead of a cure they now prefer to use the term NEDD, or no evidence of detectable disease, at a specific time-point knowing full well that a limited number of subjects will relapse and present with recurrent disease after this point. We propose using the term NEDA, or no evident disease-activity, at 15 years as a starting point for defining a cure. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a usual endpoint. In addition, the median time to the onset of secondary progressive MS is ~10-11 years (Kremenchutzky, Rice et al. 2006) and is well within the 15-year time window of our proposed definition of a cure. At present NEDA is defined using a composite of a) no relapses, or b) no EDSS progression, or c) no MRI activity (new or enlarging T2 lesions or no Gd-enhancing lesions) (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). This description is currently based on data that is routinely collected in contemporary clinical trials (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). The definition of NEDA will evolve with technological innovations and clinical practice, and in the future, it will almost certainly include MSer-related outcomes, grey matter disease activity, an index of brain atrophy and hopefully a CSF biomarker profile…..
References:
Giovannoni, G., S. Cook, et al. (2011). “Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis.” Lancet Neurol 10(4): 329-337.
Havrdova, E., S. Galetta, et al. (2009). “Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study.” Lancet Neurol 8(3): 254-260
Kremenchutzky, M., G. P. Rice, et al. (2006). “The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease.” Brain 129(Pt 3): 584-594.
Atkins et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016 Aug 6;388(10044):576-85.
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 GdGd-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.
CoI: multiple
An excellent post and very consistent with your previous posts. Do you have any plans to get the MS community behind you? Can I suggest using #ThinkCure to keep your messaging the same as your other campaigns?
Re: "#ThinkCure"Yes, I like it. You clearly are beginning to think like me. Unfortunately, when I mention the 'C-word' or cure at meetings I tend to get slapped down by my colleagues, which is why I now speak about a 'potential cure' and not an 'actual cure'. However, the promise of a 'cure' or 'potential cure' is important for pwMS. Why would you take on the risks of HSCT and Alemtuzumab unless this was on offer?
The post on Why You Get Worse Despite NEDA never mentioned 'burnout'What exactly is that?Does the shredder eventually stop?
Burnout simply refers to delayed flatlining of disease worsening. It tends to occur in younger people who have reserve and a window before ageing begins to take its toll. We really need tools to separate smouldering MS disease activity from early ageing. I have some ideas, but need to test them in clinical practice.
Re: "Does the shredder eventually stop?"Yes, I think in a proportion of pwMS treated with IRTs, in particular HSCT and possibly alemtuzumab. I am not convinced yet by the data on B-cell depleters.
Great Article Prof G. However. There seems to be a big disconnect between you and the rest of your team. For. Instance MD and Dr Karl seem to thick Ocrelizumab and caldeibine are better therapies and brain atrophy is low due to therapies starting latter than alem. This little odd for me as Ocre completely suppresses OBSERVABLE inflamation and should beat Alem hands down even if started late, eventually. So agree with your view completely. My point is how do you hope to convince others if you can't bring your own department on board. Nevertheless I believe you are the most promnient MS authority. Err I think Aaron Bosters is also up there.
Re: "…big disconnect between you and the rest of your team …"I don't think so. The difference between HSCT/Alemtuzumab and Anti-CD20/Cladribine is the former deplete both T&B cells and the latter mainly B-cells. Yes, anti-CD20 takes about 15% of T-cells and cladribine about 50% of T-cells. Clearly there is a message here and clear daylight between these two strategies. I know that my team are thinking about the difference between these two strategies intensely. Based on end-organ damage markers, including brain atrophy, HSCT/Alemtuzumab appears to be superior. Even natalizumab is superior to anti-CD20 and cladribine in this domain. Interestingly, natalizumab blocks trafficking of both T & B cells. Is there a message here?
Re: "…you are the most prominent MS authority. Err I think Aaron Boster is also up there…."Don't be fooled by social media. What links Aaron and me is that we are probably the most active MSologists on social media. I view social media as a 'soap box'. soapbox = box or crate used as a makeshift stand by a public speaker."a soapbox orator" used with reference to a situation in which someone expresses strong opinions about a particular subject."I do tend to get up on my soapbox about this issue"Social media is also an 'echo chamber' in the sense you only speak to yourself and a small number of like-minded people.Despite sounding negative, thanks for the compliment.
Have to wryly mention that Aaron references you in a positive way ProfG on his Alemtuzumab vids – concerning a question you'd asked him, as I recall.As a consumer of MS info, as a PwMS, it is my view that some of Aaron's vids are a little dubious in quality of content, but others are good quality. The ones on Alemtuzumab and on disease progression I share with family and friends who found them beneficial/accessible. Where does your previous statements concerning the possibility of delayed treatment effect for mature PwMS sit within everything you've clarified in this post? I know you were good enough back in Feb to email the MS-Base team and requested they look into the question of DMTs efficacy post age 53yrs from their real-life data set. Are you hopeful of a response within the year? An interested 'Old' who was totally convinced with the rationale to have Alemtuzumab. Received at age 53 round one/54 round two, and shortly before the study was posted on Bart's
Re: "MS-Base"They are on the case and working on ways to analyse this data. I stand firm on my interpretation about age. Age is not independent of disability and reserve capacity and hence you will see a waning of a treatment effect based on loss of reserve. The problem with the phase 3 studies that they are too short to take into account therapeutic lag and they all use the EDSS which is driven by lower limb function. I see no biological reason why somebody older than 53 years of age won't respond to DMTs, particularly when your treatment aim is preservation of upper limb, bulbar (swallowing) and cognitive function.
Thanks Prof G, F1. I find Aaron videos on ms very uplifting and inspiring as well as dealing with Ms on day to day basis with tips. As for shared decision making agreed. Brexit vote is a prime example. Why on earth would you allow average erson decide on such a complex problem! Those qualified to understand, agreed.
Aaron and I have very similar treatment philosophies and we both believe passionately about patient activation and shared-decision making. However, I am having doubts about the latter being true shared decision making simply because the field is so complex. Asymmetrical knowledge makes shared-decision making difficult.
"My point is how do you hope to convince others if you can't bring your own department on board".We are independent thinkers and you convince via argument and published comparable data… Too much data is not adequately published (meetings abstracts) nor comparable? However a testable hypothesis and a subject for a lab meetingThe scandarnavians probably have the numbers of people on early treatment with CD20 to address this and if true then great more stuff to understand and integrate.You could them up the the dose of cladribine to kill the correct T cells of can add something to ocrelizumab, do something else. The different doses of cladribine had dramatically different effects on CD4 numbers but not much difference on atrophy, Why not?Are CD8 important?Is anti-CD20 and IRT in MS? Will Roche or someone else do the studies? If they dont
Please could you explain further the latter half of this post? Is the ending missing? Thankyou.
Oops! Forgot to say that my question was aimed at MouseDoctor to expand on his 11.20pm post.
The studies with alemtuzumab were done in people with disease of 2 years duration compared to 6-9 years for rituximab and cladribineIn Sweden there is a very high use of rituximab. They have excellent registries and maybe they can integrogate their data to look at early rituximab treatment and effects on brain volume.The starting brain volume for occrelizumab was 1500cm3 what was it for alemtuzumab? We dont know?The change in brain volume 0-2 year for alemtuzumab was about -0.8% (Cohen et al. 2012) for ocrelizumab 0.5-2 year (-0.6%) (Hauser) and cladribine (-0.77%)But the key data is the normalizing of brain volume loss years 2-5 for alemtuzumab…the ocrelizumab data is not yet published you have to scrabbel about in an ECTRIMS abstract. There it looks like ocrelizumab is not puting the atrophy back to aging. In the cladribine trial the brain atrophy data is similar but the 3.5mg dose does not deplete t cells as well as the 5.25mg dose at least initially. CD4 T cells are depleted by 50% or 70% with higher dose but the CD8 are not as affected much. We have showwn from the phase II extension data unpublished by the manusfactureer but data dumped in an abstract that it is an IRT so do a head to head study of ocrelizumab and alemtuzumab and find out, if alemtuzumab is better great it helps you choose alem, if it is not by by alem as it is clearly carries more risks in the short term treatment.The people on the phase II extension data abstracts should get a backbone and insist that the data is properly published. It speaks to safety. The company don't want people to know this because they want you to take their drug every 6 months, when you may not need to. By not publishing this data it shows that the authors (yes they are very senor people) are simply puppets of the pharma marketing machine. (P.S. ProfG has done a few punch and Judy impressions in his time:-)"If they don't" should be ignored
Many thanks MouseDoctor and very best wishes for the New Year to all at Barts.
Many thanksHope all the readers have a great new year…Hopefully a better year ahead. MD2 has made it to the end..it was touch and go for a while.
As pointed out by MouseDoctor, the studies of Cladribine had an older patient population with higher median EDSS and much longer disease duration history when compared to Alemtuzumab studies. So, how can we compare atrophy results between alem and clad given these differences? Very best wishes to all.
Bom ano para todosObrigado
Gavin said: "Even natalizumab is superior to anti-CD20 and cladribine in this domain. Interestingly, natalizumab blocks trafficking of both T & B cells. Is there a message here?"But a paper just published with a small sample size of 20 showing that Tysabri does not stop the shredder!
What about benign MS? Could this be a biological cure, in other words could you be cured by your own immune system without any treatment?
Re: "could you be cured by your own immune system without any treatment?"Almost certainly. We estimate about 25% of people who are found to have MS at post-mortem were never diagnosed in life. The latter means that if they had symptoms these were not severe or characteristic enough to warrant a MS diagnostic work-up or the people had asymptomatic MS. Nobody would argue that these people did not have MS or at least benign MS. What prevented them from becoming disabled must be their own immune systems keeping the disease at bay. The same thing happens with cancers. The vast majority of cancers are dealt with by the immune system and don't cause disease. I can't see why MS would be any difference. Stated another way the majority of people at risk of MS don't get MS because their immune system prevents them getting MS.
OK. Heres idea. How about end of every year barts does peice on the biggest breakthrough in neurology. Not just on MS. And have Ms clock like the doomsday clock. To show how many minutes to midnight till cure. That is set end of every year. For me it's the pill that stopped alzhimeurs in mouse trials.
Why dont we combine alemtuzumab y natalizumab to help the body to recovery the reserves?
Once the reserves have gone..they are gone i'm afraid to say, so best not let the reserve go in the first place.
What about combining the 2 to target both CD-20 and T-cells?
Re: "What about combining the 2 to target both CD-20 and T-cells?"Yes, we proposed this 5 years ago. We wanted to give a small dose of rituximab with alemtuzumab to prevent the B-cell hyperproliferation and hopefully the secondary autoimmunity.
So for people with PPMS who have had HSCT, what can be done to preserve functional reserve? Consistent, aggressive PT, diet, both???
ALL THE WEB SITES I’VE BEEN ON THEY CAN’T EVEN DEFINE CURE FOR MS NEVERMIND FINDING ONE