For all the killjoys out there DMTs do work, i..e. they modify the course of MS and prevent you from reaching all disability milestones including the time to diagnosis of SPMS and EDSS 10.0 or death.
Please don’t listen to the zealots who are trying to spin fake news that the only treatment to prevent the development of progressive MS is HSCT; they are wrong. There are other options; the study below shows you can do it with currently licensed DMTs that are safer than HSCT. One message that is loud and clear with this data is that the earlier you treat the better and you have a much better outcome if you flip the pyramid and start on high-efficacy DMTs first-line.
↟ Figure 2
↟ Figure 3
↟ Figure 4
Brown et al. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA. 2019 Jan 15;321(2):175-187.
IMPORTANCE: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.
OBJECTIVE: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.
DESIGN, SETTING, AND PARTICIPANTS: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years’ follow-up.
EXPOSURES: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).
MAIN OUTCOME AND MEASURE: Conversion to objectively defined secondary progressive MS.
RESULTS: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).
CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies’ risks, may help inform decisions about DMT selection.
CoI: multiple
Is it just me that expected the long term spread between high efficacy and low efficacy platform drugs to be wider?
Yes and no! Time to SPMS take a long time.; the curves will diverge with time and the spread will almost certainly get bigger. The latter is how survival curves work and then eventually they will narrow again as fewer and fewer patients survive, for example in figure 2c above.
Very interesting data and post
Figure 2 c is seems odd
As it shows glatiramer acetate results after 11 years worse than placebo.
Also, from figure one I was surprised that fingolimod seems the most effective of the bunch!
It’s good to see that they have an effect but like the previous poster, kind of expected more variation between the treated and non treated
“Is it just me that expected the long term spread between high efficacy and low efficacy platform drugs to be wider?”
“It’s good to see that they have an effect but like the previous poster, kind of expected more variation between the treated and non treated”
Well that makes four of us…who dare say the Emperor has no clothes..Neuros have no drugs.
Us three and George Ebers…this fake news DMT post isn’t impressing anyone. Backfires. Boom.
The charts/graphs are horrible..real question is do you have any 50yr. long ms patients who aren’t in a Wheelchair or Institution because of these DMT’s..?
Because the old blog had a poster who went 50 years Untreated before secondary progressive..how effective are DMT if some Treated people turn progressive in 10 years..?
Ocrevus vs. Placebo
https://www.neurologia.com/img/imagenes/2018132_2018132_01%20ENGLISH.jpg
George Ebers
George Ebers may actually like this study. He always wanted the outcome in trials to be time to SPMS. This data shows that DMTs delay time to SPMS, but do not necessarily prevent SPMS.
Maybe we should restain from using wording like “real life experimemt”, “in 15 or 20 ys …” Or “potential cure” when talking about IRTs in that case?
Lessons to be learned from Corbyn dancing around indecisevness…
All goes bag to that NIH megabstudy I posted on the blog 4-5 ys ago that says drygs only work until the age of 54. We have been trying to shoot it down since.
GA is it surprising it was the best selling MS treatment?
It is said that HSCT can not only slow progression but halt it entirely for some. Have any DMTs been proven to be able to halt progression, or just slow it down?
Gavin, none of the HSCT ‘zealots’ deny that DMT’s have an effect on the progression of MS, and I don’t know a single ‘zealot’ who wouldn’t agree that MS should be hit hard and hit fast!
What’s rattled your cage this time?
The point here is that you’re talking solely about relapsing remitting MS, but the vast majority of those being treated with HSCT these days are progressive patients going overseas!
“But HSCT will not work for progressive MS!” I hear you cry. Well, that’s not what I was hearing at the international HSCT conference in Moscow last month, where many top haematologists spoke, including Burt, Saccardi, Federenko, Burman, Snowden…
Dr Saccardi specifically invited Dr Federenko to submit his data on HSCT for progressive MS to be included in the EBMT database. If that’s not an endorsement, I really don’t know what is…
Burt will also be speaking at the Mexico conference at Clinica Ruiz this month, so it certainly appears as though he feels they are valid centres for the treatment of MS. He said would welcome trials of HSCT for progressive MS to support the data already gathered.
You can listen to all the speeches and the cases for and against MS for progressive MS on the AIMS Facebook group (our logo is the purple and yellow iris – a symbol of ‘new life’ adopted by the HSCT community). We will be uploading the videos to our website and YouTube page shortly.
Merry Christmas to you and MouseDoctor! 🙂🎄
Since you were there, what’s the latest with Moscow v.s. doping charges?
Did they submit any data yet? I heard it was all lost, “cat ate it or somethin’ “
hi Alison,
I have MS and I mean no offence, but your point about “Well, that’s not what I was hearing at the international HSCT conference in Moscow last month”
I am not pro or against HSCT… but you don’t expect to go to a meeting for a specialist topic where the SMEs (subject matter experts) make their living from said topic, and for them to talk it down.
I think its always good to have a safe sense of caution and remember to be alert to the fact that the agenda of those telling you something may be different to the reasons you hope..
plenty of vascular meetings…plenty of microbiome meetings
What did Prof Ebers say? You always follow the money…
He did; George became quite wealthy playing the stock markets as a day-trader.
Not the point.
Pharma stocks 😉
Whether he did or didn’t, doesn’t change the point.
OK. thanks. Merry Christmas to you too
thanks Merry Christmas to you too
Re: “What’s rattled your cage this time?”
The implication that HSCT is different from other DMTs and that it will prevent rather than just delay the onset of SPMS.
HSCT is just a high-efficacy IRT and won’t necessarily prevent SPMS.
But Gavin, if someone who had HSCT progresses to SPMS then the HSCT hasn’t worked because it’s not halted the progression for them. If someone on a DMT eventually progresses to SPMS then that’s a success because it’s slowed down the progression.
Very interesting study. Prof G, how can we explain why fongolinod seems to be more effective than alemtuzumab on the charts ?
“how can we explain why fongolinod seems to be more effective than alemtuzumab on the charts ?”
We can’t…so clearly someone input the wrong data.
These are real life data
Selection bias; the more active / severe patients get alemtuzumab. Most of the fingolimod cases are treated first-line in Australia. This is why it is difficult to compare donkeys with pack-horses or race-horses.
A few questions Dr. G.:
1. “trying to spin fake news that the only treatment to prevent the development of progressive MS is HSCT; they are wrong”
I am no HSCT Zealot, although I regret listening to my neurologist when I was first diagnosed as I would be in much less of a current predicament. I have never heard one HSCT proponent stating it is the only treatment. It is most definitely the more efficacious treatment than current DMDs in RRMS. Why have studies not been done thus far you should ask your close Pharma ties? Probably because HSCT would “mop the floor” with all current DMDs and then they could not continue to exploit MS patients based on a comparison study which will never happen, as you well know.
2. “currently licensed DMTs that are safer than HSCT”
This is fear mongering at its best as they all cause morbidity and mortalities. I believe Dr. Atkins and Dr. Freedman, as well as Dr. Burt, have now stated that the chemotherapy used in HSCT is much less than 1%, currently at 0.3% since 2005. Do you think the highly effective DMDs don’t have similar morbidity and mortality numbers, like alemtuzumab, rituximab/ocrevus or cladribine which are also forms of chemotherapy. Alemtuzumab already is severely restricted.
3. Why wouldn’t chemotherapy in HSCT be better in RRMS and progressive MS?
It is CNS penetrant and used in CNS B-cell lymphomas and myelomas and if your hypothesis on EBV controlled B cells in follicles in the meninges of the brain and spinal cord are correct, then why would it not be more efficacious in all forms of MS. Ocrevus, Lemtrada are negligibly CNS penetrant. Cladribine is more interesting and will be interested to see Dr. KS trial results.
4. In the result from the study above, who funded this study and why is the results only looked at for < 11 years when 80% of RRMS will covert to SPMS at 15 years??? This is a very poorly done study and does not prove your point in the least.
If you eliminate the immune system of course it is going to mop the floor with something that does not. Then the issue of safety is key…and then maybe a different floor is mopped is 0.3% mortality acceptable?
If you dont eliminate the immune system i.e. non ablative, is it really better? Maybe because you are depleting more of the immune system but you need a head to head. Once you know which bit of the immune system to eliminate you can be more staelthy.
In contrast to what you think that studies wont get done, I believe the ZEUS trial should be going ahead although the new label for alemtuzumab may have thrown a spanner in the works.
Thanks for your response MD.
I would like your highly valued constructive criticism of this paper suggesting disability prevention in under 11 years and in some cases 6 years at looking at RRMS converting to SPMS. If you extrapolate this to 15 years when 80% of MS patients will convert then most, if not all will, be SPMS stage of MS? Also what am I missing in that all treated cases are worsening albeit slower than placebo?
Also, we will agree to disagree on HSCT. If I was told I could have a normal life in front of me with a 0.3% chance of dying instead of progression of MS, I would take it in a heartbeat. All DMDs/immunosuppressants come with morbidity and mortality costs and most efficacious DMDs are forms of chemotherapy already.
0.3% chance of dying…maybe you would jump there are others who would not that people still take interferons and GA suggests this
“Also what am I missing in that all treated cases are worsening albeit slower than placebo?
You aren’t missing anything..this is the Big Lie.
That MS can be managed like diabetes. The
efficacy of DMT’s are exaggerated for NYSE pharma earnings …and for Dr.s who prefer prescribe a drug known for limited effectiveness than do nothing.
One day DMT cost will go down in history books right alongside Dutch Tulips…”The term “tulip mania” is now often used metaphorically to refer to any large economic bubble when asset prices deviate from intrinsic values.”
https://en.wikipedia.org/wiki/Tulip_mania
JK Rowling isn’t missing anything either… These guys might have had a shot at Harry Potter money..if they’d of pulled off a trial in the last 10 or 20 years…instead of blogging MS subway maps to nowhere and imaginary MS treatment pyramids. No matter. This is the result.
https://www.barrons.com/articles/j-k-rowling-donates-18-9-million-to-ms-research-01568318421
Oh no no.
very sad that you think this way, I think we can be proud of our bang for buck
Just checked online and can’t find any MS trial results from the Anne Rowling Centre. Do you have any insider information to share?
I think the only trials they have done are the stem cell studies and that was an MRC trial years ago, all the rest are trials that were instigated elsewhere.
Bang for Buck Eh?
I wonder if there’s an audit?
Re: “4. In the result from the study above, who funded this study and why is the results only looked at for < 11 years when 80% of RRMS will covert to SPMS at 15 years?"
This is real-life data and 11 years is all the follow-up they have. These results are reassuring.
6 to 11 years is simply not enough to know whether a drug is efficacious in delaying or stopping RRMS progressing to SPMS. Surely, Dr. Compton and Dr. Coles or Dr. Steinman surely have this data on more efficacious drugs alemtuzumab and natalizumab respectively in Phase 4 studies?
The companys have and control the pahse IV data
G, Mouse,
When healthcare providers want to make rational decisions they calculate QALYs. (Quality-Adjusted Life Years) gained or lost.
In terms of QALYs, HSCT “mops the floor” because a .3% death rate doesn’t begin to keep HSCT from dominating every (other) DMT. And that even holds as one is factoring in costs heavily to not at all!
Furthermore, did I miss it or did you not even try to refute the argument that drugs like Lemtrada have mortality risk on the order of .3%. (13 deaths caused by Lemtrada had already been reported to the FDA by 2018. How many times that has it killed, total?)
Who are these zealots/where is this zealotry you speak of?
It was said HSCT data- Dr. Burt’s and others’- was impressive but there weren’t any randomized controlled trials. Well, now we have multi-centre RCTs.
Please, if the astounding data shown in youtube.com/watch?v=PRxmIhM4T_M is fraudulent or deceptive PLEASE provide the EVIDENCE. If not, are you not in awe?
But if all you can point out are downsides that he isn’t mentioning, without challenging the results he’s touting, why do so?
Mouse,
When healthcare providers want to make rational decisions they calculate QALYs. (Quality-Adjusted Life Years) gained or lost.
In terms of QALYs, HSCT “mops the floor” .
And I noticed you didn’t even try to refute the argument that drugs like Lemtrada have mortality risk on the order of .3%. 13 deaths caused by Lemtrada had already been reported to the FDA by 2018. How many times that has it killed, total?