ThinkSpeak: do we really need a wrecking ball to crack a nut?

Wrecking-ball or molecular tweezers; choose your poison. #ThinkSpeak #MSBlog #MSResearch

ThinkSpeak = thinking aloud

"I have said many time before the autoimmune hypothesis of multiple sclerosis may be wrong. This is why I refer to black swans, field hypotheses and viral causes of MS. I am not alone in the world when it comes to taking an alternative view of MS. Many of you will argue that I am wrong and that this position, or hypothesis, is incongruent with the effectiveness of induction treatment strategies such as HSCT, alemtuzumab, cladribine/fludarabine, etc. When you look at all the highly-effective therapies common to them all is an anti-B-cell effect, except for daclizumab which is an outlier. In other words HSCT may be simply be working via its effect on B-cells. If this is the case then the T-cell depletion, general bone marrow suppression and other off-target toxicities are simply collateral damage. Do we really need a wrecking-ball to crack a nut? Likewise, if alemtuzumab is working via B-cell depletion do we really need to collateral damage that comes with alemtuzumab's depletion and immunological changes that come from  its specific immune system reconstitution pattern (secondary autoimmunity). Do we really need a sledgehammer to crack a nut? Cladribine and fludarabine may be safer to use than either HSCT or alemtuzumab, but we would still be using a hammer to crack a nut."



"With a short-term efficacy profile that is looking very good anti-CD20 therapies must be the way to go; they work like heat-seeking missiles to take-out their target and the collateral damage from depleting B-cells seems relatively contained. This view may change with longer follow-up. What population of B cell is anti-CD20 therapies targeting? Could it be the EBV infected pool? If this is the case then we need better drugs; drugs that target EBV hence the need for the Charcot Project. More importantly, are anti-CD20 therapies enough? I suspect not. Stephen Hauser mentioned to me at ECTRIMS that many of his patients with active RRMS treated on rituximab for many years have gone onto to develop secondary progressive MS. Why? It may be that anti-CD20 therapies do not target long-lived plasma cells within the central nervous system and these plasma cells, which produce OCBs may be driving progressive disease. This is why I am so disappointed that MedImmune have put their anti-CD19 MS programme on ice; CD19 is at least expressed on plasma cells and anti-CD19 may be one way of targeting this population of long-lived plasma cells."

"People are often surprised  that I am so interested in daclizumab as a treatment for MS. Why? Daclizumab is one highly-effective DMT  that does not have an obvious upstream impact on B-cell biology. If I am right about the B-cell depletion hypothesis then how is daclizumab working in MS? If we can work out daclizumab's exact mode of action in MS we will be much further along the path of finding out the cause of MS. At present we know that daclizumab as a monotherapy seems not to be immunosuppressive in the classic sense and appears to working as IL-2 modulator. By directing IL-2 away from its high-affinity receptor to its intermediate affinity receptor it expands the population of CD56-bright NK cells. The expansion of this population of cells correlates with daclizumab's efficacy. The function of CD56-bright NK cells is complex; they are part of the innate immune response and have regulatory functions in relation to activated effector T-cells. The latter fits with the autoimmune dogma. Their other role is anti-viral. Could CD56-bright NK cells be controlling the virus that causes MS? I therefore can't wait to study the impact of daclizumab on HERV and EBV biology in pwMS. This is why I am hoping the FDA and EMA, and NICE,  give daclizumab a greenlight. Not only will it provide people with MS another option to treat their MS, but it will allow us to test the daclizumab antiviral hypothesis."

"I am sure many readers will disagree with me on many of the points above. If you do lets have a conversation or debate about the issues. I really don't believe we need wrecking balls, sledgehammers, hammers or heat-seeking missiles to treat MS. I would prefer a precision tool; a set of molecular tweezers that cause no collateral damage."


CoI: multiple

Labels: , , , , ,