Have we optimised the dose of anti-CD20 therapies to target the real MS or smouldering MS, i.e. disease progression independent of relapse activity (PIRA)?
I did an iWiMS webinar on Wednesday covering anti-CD20 therapies and the risk of COVID-19 and severe COVID-19. I covered vaccine responses and how to be vaccine-ready or vaccine responsive to a future SARS-CoV-2 vaccine if you are on an anti-CD20 therapy.
I also discussed optimising the dose of anti-CD20 therapies making the point we may need much higher doses than what we currently use to treat MS. The latter is because we have been blinkered by the impact of anti-CD20 therapy on focal inflammatory events, i.e. relapses and MRI lesions, when the real MS (disability/smouldering MS) appears to more responsive to higher doses of anti-CD20 therapies.
I re-recorded my lecture to spend more time on why these issues are important for people with MS. I have also shared my slides below.
CoI: multiple
Just found out my bloods at 6 months after year 1 of cladribine are at 0.54 for lymphocytes
They were at 0.6 at 3 months
Hey hum
Say I get covid and they see my T cells are low, will they now give me a shot of interleukin 7 to boost my T cells as they now identify low T cells with some severe covid issues?
If so is this something I need to concern myself about?
How about others on DMTs that hit T cells?
Where does interleukin 7 fit into the picture?
Could you please just explain something in really basic terms
If relapses and MRI activity are symptoms of the real MS why when you stop relapses an MRI activity is the real MS not being dampened? Surely the real Ms is dampened hence it does not cause relapses and MRI activity.
If drugs somehow stop the relapses and MRI activity but the real Ms is still continuing causing damage why are drugs still only being approved if you have relapses and MRI activity
Or if Ms still progresses regardless of stopping relapses and MRI activity why bother using any drugs in the first place?
“Why bother using any drugs in the first place?”
MS drugs, to put it in COVID-19 terms, flatten the curve. The DMTs delay the increase of disability measured on the expanded disability status scale (EDSS).
Excellent analogy
The drugs allow you to get on with life
And if you flatten the curve enough, you MIGHT even allow the body to repair stuff
You might even get through life without too much disability
Means you might even have a normal enough life
Hope my understanding is right?
Yes and no. We have to first show the strategy works. Thes are hypotheses that need to be tested.
My post below (Tom) addresses your concern.
Hi Prof G
Thank you for this. I have read in the news today about the importance of T cells in covid-19.
Am I understanding correctly that ocrelizumab depletes T cells but not enough to be a significant issue?
That is what I had always understood from your previous posts.
Does any of the T cell info change your advice to your patients? As in: no shielding if otherwise fit and well (stick to strict distancing etc) and OK to carry on dosing unless a vaccine becomes available (then consider delaying dose)?
Finally did the iwims present any data that signals any DMTs this week?
Yes, correct. The level of T-cell depletion for ocrelizumab doesn’t appear to increase your risk for viral and severe viral infections with the exception of herpes zoster, which is a latent virus.
Our advice remains the same regarding shielding; you don’t need to shield only follow the Government’s guidelines on socially distancing.
And if people have co-morbitiies? …which is why I am shielding….and about to have a year 10 daughter back at school next month by the looks of it, and a husband who still has to work in a lab….I’m becoming immune to all of this Covid stuff.
My first ever Ocrevus was postponed the week this all started (March? seems to long ago!)
Taken me best part of 18 months to actually pluck up the courage for it (after reading this blog mostly) go for it and bin the Copaxone…now I’m wondering if I should even bother.
I can’t effectively shield properly unless I leave home and move out
Re: “Finally did the iwims present any data that signals any DMTs this week?”
In Sweden being treated with Rituximab increases your risk of COVID-19 (same message as last week), but this is uncorrected data and likely to be confounded by other factors.
“The latter is because we have been blinkered by the impact of anti-CD20 therapy on focal inflammatory events, i.e. relapses and MRI lesions, when the real MS (disability/smouldering MS) appears to more responsive to higher doses of anti-CD20 therapies.“
Where is the evidence that higher dose of anti-CD20 therapies have an impact on the real MS?
If MS starts in the brain (the immune response from outside the brain is just a natural response to ongoing damage) then surely what’s important is for the anti-CD20 therapies to into the brain at higher doses than present?
The BMT study in Canada gave long term remission to many participants. Did that therapy tackle the real MS rather than just the immune response?
God luck in your work here. You are on to something and a treatment/s to tackle the real MS would be the real game changer.
What about those with drug induced lymphopenia on anti CD20 DMDs would you hold off giving higher doses even if they had evidence of progression?
As you rightly point out in the presentation, 600mg for a 60kg person is like 1200mg for a 120kg one, so what dose per kg would your ideal study pit against each other?
Also, is the idea of using CD20 depletion as induction therapy followed by maintenance treatment driven by the expectation that it would be more effective than continued CD20 treatment (if so, what is the argument for that?) or more by a consideration of cost/risk for AE of sustaining CD20 depletion?
The idea of induction and maintenance is really about efficacy and safety.
By allowing B-cell reconstitution to take place in the presence of teriflunomide we should be able to prevent EBV reinfecting memory B cells and keeping MS in remission.
“By allowing B-cell reconstitution to take place in the presence of teriflunomide”
But why choose Teri..? as opposed to all the others..?
Antiviral activity against EBV.
OK. Let me get this right. MS is after all B cell mediated disease. Just we are not killing enough B cells hence the reason Brain atrophy is still high and disability continues to acure. However, this implies Alemtuzumab is better anti B cell drug then Ocrelizumab? Because alemtuzumab is a far superior treatment then ocrelizumab and brain atrophy normalise after 2- 4 years. And i given just 2/3 times but still manage to kill more b cells then anti cd20 therapies given every 6 months! Hmmmm, does your hypothesis still add up? or is a initiative to placate pharma and win for more research grants. Not saying that’s incorrect just finding your change in view little confusing.
You need to read more posts on the blog. What controls EBV is T-cells. Alemtuzumab and HSCT rejuvenates T-cell responses and keeps EBV under control. Occasionally these treatments render patients EBV negative. This is why Atara Bio are using anti-EBV CTLs to treat MS.
Thanks prof G. We agree something else is happening that doesn’t just depend on b cell depletion. Are you suggesting we need something like Ataras early phase drug on top of cd20 therapies? The reason I suspect you can’t just use Alemtuzumab of HSCT of because dangerous side effects. Ok makes sense.
Speaking of Atara, any chance to get some insight on the recent ATA188 press release? I sadly do not think the eposter is publicly available anywhere…
They carried out the phase 1 trial on 6 people. 1 person had improved edss on 5ml, 1 person had a worse edss on 10 ml. And 20, 30 4 people had improved edss. In my opinion this trial says nothing about efficacy. As md will point out single Swallow does not mean summer is here. Also why did one person fail on 10ml when another improved on 5 ml? Meaningless trial
. They should included at least 50 people.
Bravo…as you say Shit-In, Shit Out. I think after a look see to guide proper analysis these half baked trials get us no where we want to rule things in and repeat or rule out and move one
“Alemtuzumab and HSCT rejuvenates T-cell responses and keeps EBV under control.”
And that’s why HSCT is best treatment currently for EBV in MS..and why Atara doesn’t allow anyone ever treated w/Alem. or hsct in the trial.
Unfortunate that 90% here seem to be on Ocrevus or Tysabri
which do poorly on brain atrophy.
“..long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment. ”
https://rupress.org/jem/article/201/5/805/40222/Thymic-output-generates-a-new-and-diverse-TCR
If ATARA results are the best we are going to get then the EBV idea needs abit of a re-think because the data simply is not that miraculous.
This is in response to Anonymous, May 22, but may also fit other’s concerns. I watched the Dr’s presentation and think I got the gist of it. I’ll point my MS Doc to it, next time in.
I’ll try to put a lot into a few words, to your concern. After 10 years of beta 1b, all MRI evidence for me had stopped. Continuing another 10 years with Beta 1b, everything still appearing dormant, including new symptoms, and yes, I was able to regain a majority of what I had lost. But in the last 5 years, I have slowly declined, losing some of the recuperation I had gained, but no truly new loses; & still no MRI evidence. My interpretation is either 1) as Dr has explained, some kind of “deep” (in bone) MS activity, or, 2) as has been put forward generally by many for some time- a “burned out” course of MS where older age combined with old body repairs is no longer holding up.
So, my novice opinion being self-educated on all this, is the DMTs overall are better than nothing. They “flatten” the curve. Better EDDS scores in comparison to placebo. But as seen in my case, perhaps MRI evidence is not everything. Or perhaps, I’m just getting old. Sounds like emphasis on Atrophy as indicator of disease activity is better.
Now this is where it gets more interesting- so I tried Ocrevus for a year, but did not continue with the next full infusion when covid came along (here in Trump-land). Too early to tell how that was going to go. Now I have to choose between restarting ocrevus or looking to vaccine readiness (requiring no ocrevus). I wish there was something showing non-active SPMS’rs with clinical symptoms only, benefited from ocrevus. Certainly, people benefit by not getting covid. I think I’ll go that route and avoid more ocrevus. Can live at this later stage with a bit more disability. Can’t live with death.