Depleting B cells in the CNS

Studer V, Rossi S, Motta C, Buttari F, Centonze D. Peripheral B cell depletion and central
proinflammatory cytokine reduction following repeated intrathecal
administration of rituximab in progressive Multiple Sclerosis.
 J Neuroimmunol.
2014 Aug 19. pii: S0165-5728(14)00850-9. doi: 10.1016/j.jneuroim.2014.08.617.
[Epub ahead of print

B cells and/or the enhanced inflammatory milieu in the subarachnoid space are
supposed to have a role in cortical pathology of progressive multiple sclerosis
(PMS). The efficacy of intravenous rituximab to deplete circulating B cells is
remarkable in MS, and its intrathecal delivery could target compartmentalized
inflammation in PMS. We describe the central and peripheral effects of repeated
intrathecal rituximab administrations in a patient with severe PMS. Peripheral
CD20+ B cells were reduced, while oligoclonal bands were unaffected. Several
central proinflammatory cytokines, and markers of neurodegeneration were
markedly reduced. 

The agents that affect relapsing MS all can target B cells within the peripheral (Blood) compartment. But many of these agents will not penetrate into the CNS. Some people think that progressive MS may be a problem within the central (CNS) compartment (area). So one way to look at this is to deliver B cell depleting agents into the CNS. This can be come by intrathecal delivery. In this study antibody was delivered in to the central compartment and enough got into the blood to deplete the peripheral compartment. Anti-CD20 depletes many B cells but not the B cells producing antibody (plasma cells) and so maybe you would not think that oligoclonal bands (antibodies within spinal fluid) would be depleted. But some markers of inflammation were reduced.

However is spinal deliver of antibodies a viable treatment? Well if it works one can make a case however it says why not get a drug that can deplete B cells in the peripheral and central compartments. There are already drugs that could do this, why not give them a go…Oh they are outside their patent life so pharma won’t development them. 

This is also probably the fate for rituximab.Should neuros do trials with drugs that they may not be able to get pharma to develop?

This is a debate that needs to be debated and solutions found

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  • Disappointing that oligoclonal bands were unaffected. Does that suggest intrathecal rituximab will be no more helpful than intravenous for progressive MSers?

    Also: Does the paper say anything about the MSer's progression after treatment?
    Intravenous rituximab slowed progression in younger patients with enhancing lesions.

  • Prof G, how would you rank Rituximab with regard to efficacy compared to Fingolimod, Alemtuzumab and Natalizumab? I know there is no Rituximab-trial but would you put it into the "highly effective class"? Closer to Fingolimod or closer to Natalizumab?

    I tried to find something about sideeffects. Seems to me it is generally well tolerated. I could not find anything which seems as serious as the autoimmunity-issues from Alemtuzumab or PML from Natalizumab. Did I miss anything?

    Alemtuzumab is recommended to be used as early as possible. Would you consider it for someone failing Fingolimod?

    Any idea when Ocrelizumab might become available?

  • You need anti-CD19 treatments to target plasmablasts. That should, theoretically, seriously benefit the health of PPMSers, perhaps even SPMSers.

    But no-one is genuinely pushing this strategy. Progressive MS, which really is what all MSers have at varying degrees, is the true area that needs effective remyelination treatments. That is the only way to properly treat MS. This blog need to convey more reporting on this area.

    • your info is ncorrect there are anti cd19 studies on going.

      More info on this study will surface in due course

    • For remyelination to occur you need intact neurons to myelinate so we need effective neuroprotective strategies in tandem with effective treatments to stop relapses, to save as many neurons as possible (which is a main research focus in our lab) in order for any remyelination strategy to be effective, otherwise it's putting the cart before the horse (in my opinion).

  • "Should neuros do trials with drugs that they may not be able to get pharma to develop?" Yes, if there is clinical need and pharma does not want to spend the $. Academic medicine needs to be more proactive in areas that are deemed "less profitable" by drug companies.

    • I agree but the question is how is this done?

      Whilst it may seems like a daft question but in recent times the history of neuros achievements without pharma input is……em

  • Huge though this problem is, isn't it a microcosm of our times? We throw away and waste so much: food, water, resources natural & manmade. Doesn't matter whether it's pharma or any other line of business: there needs to be a fundamental shift in how things are done.

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