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Jarred Younger's Take On The Rituximab Trials

Discussion in 'Latest ME/CFS Research' started by Never Give Up, Jul 23, 2015.

  1. Never Give Up

    Never Give Up Collecting improvements, until there's a cure.

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    This is from Dr. Younger's Lab's Facebook page.

    Thoughts?


    [​IMG]

    Neuroinflammation, Pain, and Fatigue Laboratory at UAB
    9 hrs ·
    Rituximab for chronic fatigue syndrome:

    You may have seen the study released earlier this month that showed rituximab can effectively treat chronic fatigue syndrome. The beneficial effects are reported to last for months. I recently had a chance to review the study and wanted to share some of my thoughts.

    Here is my hypothesis (which is different from other researchers) regarding how rituximab improves fatigue. B-cells are immune system cells that are ordinarily found only in the body (and not in the brain). However, when microglia in the brain are activated, they can weaken the blood-brain-barrier and let in the B-cells. Once inside the brain, B-cells cause inflammation that lead to pain and fatigue. Rituximab depletes the B-cells in the body. Because the B-cells are depleted in the body, there are no cells left to reach the brain and cause inflammation.

    The response rate was very good, with 64% of participants showing a significant clinical improvement of symptoms. That number is very interesting because it is the same response rate I see when I use low-dose naltrexone (LDN) with fibromyalgia. I am guessing that LDN and rituximab provide two different paths to reaching the same goal: stopping neuroinflammation. LDN gets into the brain and calms down the microglia so that the blood-brain-barrier gates remain strong enough to keep out the B-cells. Rituximab depletes the B-cells so they cannot reach the brain, even if the gates are damaged.

    There are some negative aspects to mention. The study is small, which means we need to see larger replications. It was open-label, meaning that the results are not controlled for placebo effects. There were some adverse events such as upper airway infections, an allergic reaction, and a temporary worsening of symptoms in some participants. Still, the results are encouraging and reinforce what this group has been reporting for the past few years. The technical aspects of the study look good to me, so I will be very interested in seeing what comes up next for this drug.

    I’m providing a link to the original publication below (there is a button to download a pdf version). It has also been discussed previously a few times by Cort Johnson.

    http://journals.plos.org/plosone/article…

    Jarred Younger

    [​IMG]
    B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase...
    Background Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown...
    JOURNALS.PLOS.ORG
    28 Likes2 Comments17 Shares

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  2. Mary

    Mary Senior Member

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    @Never Give Up - I have no idea of the validity of his hypothesis, though it's intriguing, and look forward to hearing from those who are more knowledgeable about this DD - thanks for posting!
     
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  3. user9876

    user9876 Senior Member

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    I'm not convinced by his hypothesis because of the timings. As I understand it Rituximab kills b-cells quickly but the delayed response suggests that the cause is due to antibodies no longer being produced and existing numbers reducing.

    That said on other threads http://forums.phoenixrising.me/inde...nflammation-in-me-cfs-and-fibromyalgia.38739/ I think there has been discussion around ideas of microglia activation Rituxmab and things like LDN
     
  4. adreno

    adreno PR activist

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    I'm not a fan of his activated microglia hypothesis. Activated microglia is found in many diseases without causing the symptom picture seen in ME/CFS.
     
  5. user9876

    user9876 Senior Member

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    I think the hypothesis also includes something about the areas of the brain where the activated microglia are and hence the systems within the body that changes in signaling may effect.
     
  6. JPV

    JPV ɹǝqɯǝɯ ɹoıuǝs

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    I found the video pretty compelling...



    He says that he believes his theory only applies to a subset of those afflicted with FM/ME/CFS. 60% of the participants, in a 20 day study that he conducted, showed an increase in leptin that correlated pretty closely to their increase in fatigue. I find it very interesting that that's the same percentage that also responds to both LDN and Rituximab therapies. There's also a brief mention on how LPS fits into his theory.
     
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  7. Sasha

    Sasha Fine, thank you

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  8. Snow Leopard

    Snow Leopard Hibernating

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    His 'hypothesis' is far too vague to have much explanatory power. Makes me want to start a discussion on what a 'hypothesis' for ME or CFS needs to explain and why many proposed hypotheses are too vague or inherently incomplete.
     
  9. A.B.

    A.B. Senior Member

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    Do you think the Fluge and Mella hypothesis is good enough?
     
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  10. Snow Leopard

    Snow Leopard Hibernating

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    No.
     
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  11. Gijs

    Gijs Senior Member

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    I guess you must find B cells in spinal fluid then?
     
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  12. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    I was wondering.. As Fluge/Mellla hypophesise that antiboodies are somehow disrupting endotheliel cell-function, could this process induce the proposed overactive microglia state, as the blood brain barrier is lined with endotheliel cells?

    Cause then I suppose the broad spectrum of symptoms is a bit more understandable.. E.g exercise intolerance due to muscles not being surrounded with functioning endotheliel-cells, brain fog due to overactive microglia AND disrupted endotheliel cell-function..

    Just some thoughts.

    Apologies in advance if the above includes some misunderstanings of physiology.

    http://www.ncbi.nlm.nih.gov/pubmed/25404894

    "the endothelium can regulate the state of microglial activation"
     
  13. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    I dont quite understand the following, but I thought it might be relevant, if anybody competent is keen to explain.. :)

    "In normal conditions, neurons and glial cells interact together to promote the homeostasis of the brain. When an injury occurs in the brain, microglia and astrocytes are capable of producing cytokines and chemokines and stimulate the adhesion molecules on ECs, allowing the migration of myeloid cells from the blood into the brain. In particular, microglial cells become activated with LPS stimulus and produce ROS through the action of NADPH oxidase, TNFα, IL-1β, that impairs BBB function altering the expression of important molecules in the BBB integrity, such as ZO-1, claudin-5, occluding and P-gp. CD200-deficient mice showed an increased BBB permeability that possibly favors T cell entrance in the brain followed by an increased IFNγ expression that activates microglial cells and enhance the release of microglial activation markers including TNFα, IL-6, contributing to keeping the BBB injury."

    fncel-08-00362-g0002.jpg
     
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  14. JamBob

    JamBob Senior Member

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    N = 1 but I've been taking LDN for a couple of years. I don't feel it has any meaningful impact on PEM, orthostatic intolerance and the attendant brain fog at all.

    The reason I keep taking LDN is that it provides me with deeper sleep and I generally feel "better" at the baseline when I sleep well as compared to when my sleep is disrupted. But I think that would be the case for anyone who has sleep problems. I wouldn't see LDN as a very effective treatment for CFS/ME. However I don't have fibromyalgia, so can't comment on how it works for that.

    I would hope that Rituximab would be more effective than LDN for CFS/ME.
     
  15. msf

    msf Senior Member

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    This is a little off topic, but from my own experience, and my understanding of the work of Maes and De Meirleir, LPS is going to be important, but Younger sort of passes over it without making any suggestions about how it may be involved in the process.
     
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  16. Never Give Up

    Never Give Up Collecting improvements, until there's a cure.

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    Well now this is interesting...

    http://www.ncbi.nlm.nih.gov/pubmed/23160197

    J Clin Invest. 2012 Dec;122(12):4533-43. doi: 10.1172/JCI63842. Epub 2012 Nov 19.
    B cell exchange across the blood-brain barrier in multiple sclerosis.
    von Büdingen HC1, Kuo TC, Sirota M, van Belle CJ, Apeltsin L, Glanville J, Cree BA, Gourraud PA, Schwartzburg A, Huerta G, Telman D, Sundar PD, Casey T, Cox DR, Hauser SL.
    Author information

    Abstract
    In multiple sclerosis (MS) pathogenic B cells likely act on both sides of the blood-brain barrier (BBB). However, it is unclear whether antigen-experienced B cells are shared between the CNS and the peripheral blood (PB) compartments. We applied deep repertoire sequencing of IgG heavy chain variable region genes (IgG-VH) in paired cerebrospinal fluid and PB samples from patients with MS and other neurological diseases to identify related B cells that are common to both compartments. For the first time to our knowledge, we found that a restricted pool of clonally related B cells participated in robust bidirectional exchange across the BBB. Some clusters of related IgG-VH appeared to have undergone active diversification primarily in the CNS, while others have undergone active diversification in the periphery or in both compartments in parallel. B cells are strong candidates for autoimmune effector cells in MS, and these findings suggest that CNS-directed autoimmunity may be triggered and supported on both sides of the BBB. These data also provide a powerful approach to identify and monitor B cells in the PB that correspond to clonally amplified populations in the CNS in MS and other inflammatory states.
     
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  17. Bob

    Bob

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    What is 'LPS' please?
     
  18. A.B.

    A.B. Senior Member

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    Lipopolysaccharide.
     
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  19. Scarecrow

    Scarecrow Revolting Peasant

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    In a few sentences, if you can, what do Maes and de Meirleir say? Thanks
     
  20. jimells

    jimells Senior Member

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    Like @JamBob I tried LDN. I gave up after six months because it had no discernible effect.
     
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