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.
15 thoughts on “To B or not to B”
Again a very interesting post. It does answer many questions. So then again what would it be outcome for Spms when given hstc vs Cladribine? Is hstc too more advantageous?
Yes, on average HSCT is superior. The majority of patients go into longterm remission and normalise their brain volume loss. I suspect some of the HSCTers are cured. How many? Too early to tell, but at least the experiment has started.
Thanks i really appreciate your answer. Let’s hope for a quick settlement of this ideas/ concepts /findings into scientific community for us sufferers to find a positive outcome/treatment before it is too late. Exciting times though.
“Let’s hope for a quick settlement of these ideas…”
Unfortunately nothing happens in a quick way. Look at the HSCT study that was recently in JAMA Neurology. The study took 12 years.
Very interesting. Thanks for sharing. I will read, digest and think.
At the end of the day adoption of any treatment is a slow process and is data driven. The data has to be good quality. The reality at the moment is the quality of HSCT data as a broad treatment for MS is simply not good enough, in particular its relative efficacy and risk-benefit profile relative to other DMTs, to result in high adoption rates.
“the need for an EBV vaccine for MS prevention trials”
Yes, yes, yes!!!
It’s so frustrating that this takes so long! When you think that the Russians landed craft on Venus in the 80s – where it’s 400+ degrees C, rains sulphuric acid and there’s 90 times the atmospheric pressure of Earth – and took pictures! And now the Chinese have germinated cotton seeds on the other side of the moon! But we still fumble about with the fundamentals of MS! $%#@£&!
Thank you for your work.
“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. ”
Doesn’t this contradict what you said earlier in the post? MS is one disease and can be treated effectively as a whole with the right approach. This is what we have won with HSCT and the patients who respond well to Alem. depletion: MS is not an inflammatory-demyalinating-neurodegenerative etc disease and does not need a drug for each of these things (of course a today’s PMS patient would need these support drugs). MS is one disease and if treated early and effectively can be almost cured, or at least retreated the same way if needed.
“B-cell therapies don’t match HSCT, alemtuzumab and natalizumab when it comes to downstream end-organ damage markers,”
Natalizumab, even if it has better results from O. it doesn’t stop the shredder (recent study), so it’s shouldn’t be put next to the other two at the context of this post.
“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. ”
If B-cell therapies had a curative effect, it could be a win concerning the cause of MS. For the moment EBV stays just a link to the disease.
I’m experiencing worsening despite Cladribine treatment. I assume the MRI would need to show activity to be eligible to change treatment or would I be expected to try another round of Cladribine? What level should my lymphocyte count reach to safely move onto something more effective like Alemtuzumab? Thankyou for your informative site.
This might be the reason why we can’t figure how EBV works, why B-cell therapies are not enough, where T cells start to implicate and why antiretrovirals probably work better than all DMTs.
“A new study reports herpes virus utilizes ancient RNA to proliferate, mimicking the same process tumors have been found to manipulate. The findings could have implications for new treatment options and also may shed light on neurodegenerative diseases.
The researchers found that herpes viruses appear to manipulate an ancient RNA species that originated several million years ago, called human satellite II RNA (HSATII RNA). HSATII RNA is normally inactive, but both herpes viruses and cancer cells have essentially learned to activate it, using this RNA to manipulate their environment to help them invade the body and grow.”
A change of season
Can I switch from ocrelizumab to lemtrada ?
Yes, someone with MS can switch from ocrelizumab to alemtuzumab, but they run the risk of increasing the level of immunosuppression post-alemtuzumab. On the positive side, the B-cell depletion due to the persistent effect of ocrelizumab may prevent the B-cell overshoot and delay B-cell recovery post-alemtuzumab. We have hypothesised that this may reduce the risk of secondary autoimmunity.
Thanks for the info Prof G.
What would the washout be or would it depend on my B cell count before I could start lemtrada ?
Thanks Prof G.
What would be the washout or would I need to wait for B cells ?