After my #1 highlight #ECTRIMS2019 post, I was sent an email by Antoinio Scalafari, a like-minded colleague, to remind me of their real-life data at Imperial College on alemtuzumab in clinical practice. It mirrors the trial experience and needs a platform for discussion (see below).
In parallel, I heard via the MS grapevine that the MS community does not appreciate me questioning the ethics of the DELIVER-MS and TREAT-MS Trials. Why not? These are pragmatic trials to compare escalation therapy with the strategy of flipping the pyramid (high-efficacy therapy first-line).
Giovannoni. Do we have equipoise when it comes to how we treat active multiple sclerosis? Lancet Neurol. 2019 Jul 30. pii: S1474-4422(19)30227-3. doi: 10.1016/S1474-4422(19)30227-3.
Don’t I have a right to an opinion? I finish my commentary with a simple question for the trialists: ‘The real litmus test for the investigators of the DELIVER-MS and TREAT-MS trials is the question they should all ask themselves: “If I had multiple sclerosis, how would I want to be treated?” Given the evidence, patients deserve the choice of being treated with a high-efficacy DMT first-line’.
Why shouldn’t MSers with active MS not have the option of being treated with alemtuzumab, or for that matter HSCT?
CoI: multiple
What I still fail to understand is why would patients with Active MS NOT be given the chance to start with Alem. or HSCT first line? Aren’t the “side effects” of worsening, irreversible disability due to MS much worse than any potential side effect of serious treatment?
Yes and no; it depends on a lot of factors including your worldview and the worldview of your neurologist. Using a sledgehammer like HSCT is not really a solution for all things MS; a large number of MSers fail HSCT with breakthrough disease activity.
Apologies of I am incorrect. Didn’t you say you’d go for HSCT if it were you?
My worldview as a simple patient is that HSCT is the only thing that has the potential to stop if, if not permanently.
Everything else are chemical brakes with varying degrees of efficacy.
I want to stay alive long enough that I can say that I had MS and not that I have MS.
a large number of MSers fail HSCT= 20-30%
Or…looking at it like an MS patient, which I wish more medics would, 70 to 70% succeed.
Though I doubt it is a pass/fail scenario and that you may be oversimplifying it.
Imagine having MS? Have you? Worth a punt to me.
“A large number of MSers fail HSCT with breakthrough disease activity”
This is totaly wrong and you know it 🙁
In the Italian experience, at 15 years after aHSCT, almost 60% of 160 evaluated patients did not experience disability progression.
https://ipp-ean19.netkey.at/index.php?p=recorddetail&rid=1ae237a5-63e7-46c5-be89-0e4f00fbfaec&t=browsesessions
Ean 2019 (the conference you were in)
Conclusion: This case-control study suggests that aHSCT suppresses inflammatory activity in MS more effectively than alemtuzumab. Despite longer disease duration and lower pre-treatment relapse activity in the alemtuzumab group, which hypothetically should be associated with less inflammatory activity, more MRI activity and relapses were observed in this group in comparison to aHSCT treated patients.
http://www.professionalabstracts.com/ectrims2019/iplanner/#/presentation/1377
Ectrims 2019 (another conference you where in)
Also how can a patient get advice from you, since you have conflit of interests in Alemtuzumab drug ?
You have manifest manny times your disapointment towards Ema banning a drug that costs 65000 euros a year ?
Maybe (just maybe ) that will hit your pockets too ,given your extensive conflit of interests
Every patient that need Alemtuzumab should realize this facts when reading your posts
Also Dr Antonio scalfari also received money from Genzyme (maker of alemtuzumab)
Conflict of interest
Dr Scalfari receives research supports from the UK
MS society and received personal compensation for
speaking activities from Teva and Genzyme.
Like you said a like minded friend
https://www.researchgate.net/publication/283035695_Multiple_sclerosis_relapse_phenotype_is_an_important_neglected_determinant_of_disease_outcome_-_NO
I am a bit baffled by your binary approach to CoI. You seem to be suggesting that the act of working for a company immediately and irredeemably corrupts that person. Anything they say or do realting to the company is not to be trusted.
If a policeman is paid by the government then your argument follows that at no time would they ever act against the government. Yest we see many times when the police do just that.
The vast majority of Doctors (and police officers) do it because they love their jobs, not to get rich. They are, however, paid enough to make them hard to corrupt.
It is a pretty cheap shot to just say/imply that an honestly stated CoI = immediate untrustworthiness. Habeus corpus?
Excellent. Keep pushing!
Thanks. We need all the support we can get.
The ocurrence of relapses and new mri activity was similar in the two group
Relapses and mri activity dont matter ???
Probably not. Relapses and MRI activity are not MS; I have posted on this endlessly before. MS is a chronic smouldering disease that shreds the brain. Relapse and MRI activity represent the immune response to what is causing MS.
According to Prentice’s criteria for surrogate outcomes both relapses and MRI activity fail as a surrogate outcomes, which is proof that they are no the disease.
“MS is a chronic smouldering disease that shreds the brain. Relapse and MRI activity represent the immune response to what is causing MS.”
It seems every year the understanding of MS changes and the disease gets worse. Is it time to reflect on all the Professors / MSologists who were praised for their contributions to research in the past, but it would appear now that (1) they didn’t understand the disease at all and (2) their work diverted research down the wr
“MS is a chronic smouldering disease that shreds the brain. Relapse and MRI activity represent the immune response to what is causing MS.”
35 years ago I took a friend with Bells Palsy to a neuro. My friend told the neuro she had glandular fever 2 years earlier. The neuro noted that GF was linked to MS and told my friend to monitor any changes. Why 35 years later is the same connection being made? There is slow and MSology slow!
Should all the MSologists given prizes over the last 50 years give them back? Their focus on relapses and MRI distracted research from the real disease.
Should MD1 get his P45? I always thought EAE was a waste of time. As animals don’t get EBV and EBV is the likely cause of MS, EAE was a hopeless model to study MS in humans. MaD1 is the mouse version of Pol Pot.
Let’s expedite the EBV link to MS ie come up with highly effective anti-vitals. We don’t want to see 30 more years of interferon v GA trials, or endless debates on T v B cells. EBV is the driver of MS. Eradicate the virus and eradicate MS.
WELL SAID
Us with this brain shredding don’t have the luxury of waiting DECADES more for the “cure” or as near to the cure as they can get.
PUT ME ON A TRIAL FOR EPSTEIN BARR treatment.
Who starts these trials?
The problem is that EBV is often in its latent form, which is difficult to eradicate because so few antigens are expressed that would alert the immune system to attack an infected cell. But one of the proteins expressed in EBV latent cells is the EBV-encoded protein EBNA1. We developed a small molecule drug that targets EBNA1, which showed promising preclinical results (https://www.ncbi.nlm.nih.gov/pubmed/30842315). The drug is currently in Phase I clinical trials for patients with advanced nasopharyngeal carcinoma, a head and neck cancer. If it continues to show a promising safety profile, it would be interesting to study the drug in MS patients.
So you have to ask Mouse Doc
I thing he said manny time” relapses are important dont have it”
“Relapses are not good for you”
So if you have relapses it is a predictor of your disability in the future. Don’t have relapses and then maybe disability will not develop but if you are relapsing on therapy then it is worse news if you are not on therapy so maybe we need to change therapy if they are not working propertly.
https://multiple-sclerosis-research.org/2016/05/relapses-are-not-good-for-you/
Fine tune the “colective cyborg” 🙂
Yes, our positions on this are not incompatible. If you have MS and your disease is not under control your immune system may remind you of the fact by forming new lesions and/or causing relapses. But this is not necessarily the case; slowly expanding lesions, cortical plaques, etc. or smouldering MS occurs in the absence of focal MRI activity and relapses. This is why you can be NEDA-2 and getting worse. You can be NEDA-2 and your brain could be shrinking at 2-7x the normal rate.
In the placebo arms of controlled trials, relapses and MRI activity don’t predict disability outcomes. If relapses and MRI were the disease they would predict outcome in both arms of the trial.
Clifford Reed MD. Neurology–Tower Health System–West Reading, Pennsylvania, USA
I totally agree with Dr Giovannoni about inverting the treatment pyramid, as I do for all of my new MS patients. I do not use Interferons or GA anymore. We have no biomarkers as to who will be a hyperesponder to these original injectables. Prognostically for NEDA, or lack of it, 10 years later, look at Dr. Cree’s Epic Study, which was almost entirely injectables. NFL, serum SIMOA method, agreed, may be, as you Dr G, or someone, said, may be the “sed rate” for MS neurologists. Yet, NFL may be more of an inflammatory biomarker than a degenerative biomarker? Those of us who know the modern MS era highly active DMT’s well, can risk mitigate, and sequence, these DMT’s rather safely, in my opinion. When an MS patient loses ground from the unseen entire CNS degenerative ( “shredding “- past, present and future) and inflammation ( “slow burn”, past and future, and initially “fast burn”, at clinical presentation ), we Neurologists can’t get that back, except possibly, occasionally, modestly, from Alemtuzumab and HSCT. I had one very recent chronic MS patient significantly improve her 4 limb, many months of, progressive weakness, dysphagia, and retinal? worsening vision, on chronic Tysabri ( Blocking Tysabri Ab negative ), on oral Cladribine ( Mavenclad )!!! Lastly small, lipophilic DMT’s like Cladribine, and the new improved MOD’s ( Siponomod, Ozanimod and Ponesimod ), should be used early, to work peripherally, and also enter the CNS compartments, to combat all of the “salami sliced” MS phenotypes, which are one disease, past, present and future. Don’t just attack the disease peripherally (I think relapses are invited from within the forever degenerative-inflammatory brain ), but also attack these autoreactive smorgasbord of innate and adaptive cells where they forever hide, plan, constantly talk to each other, and attack.
Sorry about my verbal diarrhea, logorrhea, etc., on this issue, in defense of Dr. Giovannoni.
Dear Gavin,
As a pwMS your remark, “If I had multiple sclerosis, how would I want to be treated?” is THE most fundamental yet often overlooked question that researchers seem to fail to ask themselves.
I remain amazed at the lines some of your less *ahem* active and informed colleagues peddle to their frightened and credulous patients about modern MS treatments.
Keep fighting the fight. Thank you
PS: when I return from Nepal and have avoided the Dengue outbreak I will be agitating for HSCT before I fall to a degree of disability that I want to avoid.
Wondering why you attempt to dissuade patients from going overseas and having HSCT? For the majority of MS patients, it is probably the most effective treatment available. Even those of us who have primary progressive MS will have a 70% chance of some amount of effectiveness, including even the amelioration of some of our disability and ongoing symptoms such as severe fatigue. This is definitely the best track record out there. If I had the money and was accepted, I’d be running the Russia or Mexico myself . That is of course, if I could run, which of course I can’t, since if I can no longer walk well. People who are themselves not living with creeping paralysis, really cannot begin to comprehend the cruelty of this disease, as we watch ourselves continually lose function. And still no effective treatment ocrevus being barely efficacious.
Re: “Wondering why you attempt to dissuade patients from going overseas and having HSCT?”
Some BMT centres are run by quacks wanting to make a quick buck. They don’t use myeloabalative doses of chemotherapy and we have no idea how good they are when it comes to handling stem cells etc. However, saying this there are many reputable private BMT units who are transparent and do what they say they do. Therefore, it is about quality, etc.
Why do regulators make us jump through hoops to qualify for the most effective treatments?
My guess is as good as yours 😉
This is a genuine question….When people are being treated for cancer, do they start with the lowest of the low in terms of treatment, or do they go for the big guns straight off the bat?????
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Who are the “ms community”?
Do any of them actually have multiple scerlosis?
They don’t like what you are saying?
SO WHAT!!!! They aren’t being slowly paralysed, or going blind, or peeing themselves, or messing in their pants so what the heck would they really know?
If only all medical professions put their patients and in your case other people with the same disease, first, then we wouldn’t be so frustrated with the sheer apathy that is shown to MS.
All the big “socities” are now just money spinners. How much are the CEO’s of these charities on?
There is a post called Philanthropy Manager at one of these big ones who is on THIRTY SEVEN THOUSAND a year. There’s a lot of bucket shaking, picnics, fund raising gone into that salary isn’t there? It’s OBSCENE.
https://www.indeed.co.uk/cmp/Ms-Society/salaries
Or…looking at it like an MS patient, which I wish more medics would, 70 to 70% succeed.
Though I doubt it is a pass/fail scenario and that you may be oversimplifying it.
Imagine having MS? Have you? Worth a punt to me.
70-80%
37k is a pretty mediocre salary in London these days. My concern is 37k hardly attracts the calibre of person needed to go and twist the arms of the philanthropic bunch.
$527,970 Cynthia Zagieboylo president to ms society of USA
https://www.charitynavigator.org/index.cfm?bay=search.summary&orgid=4189
Uk Multiple Sclerosis Society *2 Mike O’Donovan *18 85,000 £
https://www.theguardian.com/society/salarysurvey/table/0,12406,1042677,00.html
$527,970 Cynthia Zagieboylo president to ms society of USA
https://www.charitynavigator.org/index.cfm?bay=search.summary&orgid=4189
Uk Multiple Sclerosis Society *2 Mike O’Donovan *18 85,000 £
https://www.theguardian.com/society/salarysurvey/table/0,12406,1042677,00.html
😦
Mike O’Donovan left the MS society years ago.
Clifford Reed (MD) mentions risk mitigation in his reply.
How is it that this is so rarely acknowledged by the neuros still pursuing the escalation model of treatment?
When you have MS you already live with a monster guaranteed to produce a loss of yourself in vital ways. Treatment is risky, but some of which can be avoided or alleviated.
It’s nice to see a response in support from over the pond. Wish there was far more evidence of it here in the UK and elsewhere. Good luck with trying to convert to save brain and inverting the pyramid Gavin, especially as it appears you’ve still an uphill battle on your hands.
You did not publish my comment?
Why
I think the “inverted pyramid” model is accepted by those neurologists who specialise in MS. At least, that has been my experience here in Australia. General neurologists are less inclined to take on the associated monitoring and highlight the risks rather than the potential benefits. Again, this has been my experience. Given this is experience of 3 neurologists (1 general and 2 who specialise), I don’t know if it is reflective of the overall speciality.
TROY
that was very informative.
THANK YOU!
(The problem is that EBV is often in its latent form, which is difficult to eradicate because so few antigens are expressed that would alert the immune system to attack an infected cell. But one of the …………….)
Hi folks, just to say as a PWMS I thank all of you for reading, keep abreast of things in the MS world and a huge thank you to Prof G for continually living and breathing MS! I live with the disease which has affected every part of my life. It is there all the time and I truly believe it is smouldering away and MRI/tests carried out annually – do not correlate to how the disease affects the person. How is it that the heat, from the sun or heat blanket can lessen the gnawing pain? If my limbs were warmed up everyday I would be able to cope a bit better. Sorry to bring this up, but if I can’t go to the bathroom everyday, this has a huge impact on my mobility & well being generally. Why is that? How come I can walk around my home for a few hours in the day (not consecutively) without my stick and other days I can’t? My nervous system feels like its been abused & is so sensitive, I feel my heart pumping away from tinnitus, burning pain in my neck and back of my scalp and I feel the blood (sensationally) running through my veins. Loud noises, stress, worry, grief, early morning (not enough sleep) & food, along with dark moods that I sometimes struggle to come out of. Don’t give me medication to numb it all and push it to the background (their side effects making me feel so much worse) – look at new ideas, blood, digestive system, Epstein virus, herpes & other neurological diseases and problems. I want to see my old age in with dignity and not being a burden to anyone. My brain is working (I think – who knows!) now, 2019, and I want to help myself. Too many choices for DMTs & qualification, confusing outcomes, complicated comparisons & side effects that seem not be so important to HCPs but possibly devastating to an PWMS. If HSCT is the way forward & there are possibly ways to increase its effectiveness (70-80%) – contact the MS Society in Scotland. JK Rowling has given them a lot of money. Surely some of it can be used to help with looking for a cure and using HSCT or hardline therapies that are proven to be the most successful, for MS patients. Let it not be a postcode lottery too. Talk to each other, get rid of some of the therapies that aren’t helping. Be brave and list a few that if you had MS – this is what you might consider? As said over again (Prof G) – if it were known that the disease is smouldering all the time and depending on your age it might become more aggressive – lets try this to see if it helps! Shout loud – all you HCPs – we need to get MS to the frontline now. Don’t lets wait for (hopefully not) another celebrity to highlight this disease and educate. We can do it if we try something new. Be bold and go for it!
Is it our ur neurologists ,we should be telling that we don’t want to continue on things like Copaxone and insist we want HSCT?
If enough of us did it, who would sit up and take notice?
We need to know who it is we should be persuading/telling that we want this…. but nobody will tell us WHO WE ARE SUPPOSED TO BE ASKING because we don’t know who to ask about who we should be asking.
I wish a medical professional would answer this…..any takers?