Premission to repost by Prof. Gavin Giovannoni There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level. Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc. @Jonathan Edwards I find this interesting as it relates to Riuximab for being underpowered to stop PPMS as for the inability to deplete B-cells in CNS Anti-CD20 trial for Intra thecal Rituximab started whilst another stopped for lack of efficacy Today we have a B cell flavoured day at ACTRIMS as CD20 depletion is at the forefront If one person has an idea another is having it at the same time. Leptomeningeal inflammation and Intrathecal Rituximab in Progressive MS Dr. Peter A Calabresi, MD, Johns Hopkins University, Baltimore, MD While many treatment options exist for the relapsing form of MS, there are no effective therapies for progressive MS. Pathological studies have shown the presence of leptomeningeal inflammation (LMI) in people with MS and it is more prevalent in primary and secondary progressive MS. LMI is linked to increased gray matter demyelination and increased sub-pial lesion load, suggesting a possible role for LMI in disease progression. Identifying this process in vivo has been a challenge, but recent studies have shown that time-delayed post-contrast FLAIR sequences can demonstrate leptomeningeal lesions that correspond to areas of inflammation with lymphocyte aggregates seen on autopsy. These lesions appear to remain stable over time and are seen more frequently in people with progressive MS. Our data suggest that in the late stages of the relapsing remitting experimental autoimmune encephalitis (EAE) model in SJL mice, contrast-enhancing lesions emerge in the meninges overlying the cerebral cortex. These lesions persist over time and consist of B and T lymphocytes, suggesting a process that may be similar to LMI seen in people with MS, which could facilitate screening of therapies designed to target this type of inflammation. Since anti-CD20 is already FDA approved and has been given intrathecally (IT) to people with MS, we have commenced a clinical trial of IT Rituximab in people with progressive MS who have two baseline MRIs demonstrating leptomeningeal enhancement (LME). Since LME is a persistent process for years, unlike white matter enhancing lesions, any reduction of LME on MRI would be meaningful. The design of the clinical trial and enrollment to date will be discussed. But as a trial starts another is stopped prematurely because it isn't going to work Intrathecal Rituximab in progressive MS stopped for insufficient inhibition of CNS inflammation: a randomized, double-blind, placebo-controlled studyDr. Mika Komori, MD, PhD, Dr. YenChih Lin, PhD, Dr. Irene Cortese, MD, Mr. Andrew Blake, Ms. Joan Ohayon, CNRP, Ms. Jamie Cherup, RN MSN CRNP, Dr. Dragan Maric, PhD, Dr. Peter Kosa, PhD, Dr. Tianxia Wu, PhD and Dr. Bibiana Bielekova, MD, National Institutes of Health, Bethesda, MD Background: The lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS) may be caused by the unreachable compartmentalized inflammation in the central nervous system (CNS). Objectives: The double blind combination of Rituximab by IntraVenous and IntraThecal injection versus placebo in patients with Low-Inflammatory Secondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: 1. Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and 2. If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction? Methods: Patients aged 18-65 years were randomly assigned (2:1; randomization sequence table balanced for age) to rituximab (n=18) or placebo (n=9). Protocol-stipulated interim analysis of serum and cerebrospinal fluid (CSF) biomarkers in patients who completed the induction dose of study drug quantified the efficacy of B cell depletion. Results: The selected rituximab regimen failed to reach criteria for continuation of the trial. Changes in B cell-related CSF biomarkers (soluble CD21 [sCD21] and B-cell activating factor [BAFF]) occurred only in the active-treatment arm. While the mobile pool of CSF B cells was depleted by a median of -79.71% (p= 0.0176), B cells in CNS tissue were depleted inadequately (~-10-20%, p<0·0001). Consequently, the T cell specific CSF biomarker sCD27 also decreased only slightly (-10.97 %, p=0.0005), while a marker of axonal damage, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement and paucity of cytotoxic CD56dim NK cells contribute to decreased efficacy of rituximab in the CNS. Conclusion: Biomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that the RIVITALISE trial would be underpowered to reliably measure efficacy on clinical outcomes. COMMENTS: In other trials of intrathecal rituximab it shows that most of the antibody put in the CSF ends up in the blood and it depletes the B cell pool in blood. However eliminating B cells from the CNS is not achieved Is the intial trial doomed even before it starts? Again 3-4 underpowered studies verses a joined-up definative answer...same old same old:-( If you are going for this approach would it not be best to target the Plamsa cells which do not express CD20, ensuring that the antibody is complement fixating and that complement s around and not killing by Antibody-dependent cellular cytotoxicity that need other cells to do the killing Reactions: Posted by MouseDoctor at 07:00 7 comments: AnonymousFriday, February 19, 2016 11:17:00 am What is the evidence that B-cells in the CNS is driving the progressive phase of the disease? It seems maybe this is not the culprit, so even if you could eliminate oligoclonal bands in progressive disease (not likely with any therapy) it seems maybe this is not the problem in this stage of the disease. Reply Replies MouseDoctor2Friday, February 19, 2016 11:45:00 am Some evidence for you. https://brain.oxfordjournals.org/content/135/10/2925.long https://brain.oxfordjournals.org/co...8977d9846b342592c405d14c&keytype2=tf_ipsecsha AnonymousFriday, February 19, 2016 12:17:00 pm Just read the first abstract and nowhere does it indicate B-cell dysfunction is the driver of progressive disease. "Profound microglial activation and reduction in neuronal density was observed in both the lesions and normal appearing grey matter compared with control cortex." I think if I took the time to read your other links I will come to the same conclusion. MouseDoctor2Friday, February 19, 2016 12:20:00 pm Goes to show you should read further than the abstract then ;-) What exactly do you mean by B cell dysfunction? AnonymousFriday, February 19, 2016 12:42:00 pm I guess the question is if you eliminate all of the b-cells (plasma cells) from the CNS, will this stop the progressive phase of the disease. If these B-cells are responsible for generating oligoclonal bands, if you can delete them this would stop progression. But from what I have gathered, the progressive phase is driven by chronic activation of the innate immune system such as microglial. MouseDoctor2Friday, February 19, 2016 12:47:00 pm That indeed is the question, which needs addressing. You're right that the progressive phase involves activated microglial cells which also have Fc receptors which detect immunoglobulin and stimulate phagocytosis. So the presence of immunoglobulin from long-lived plasma cells in the CSF could be a driver of progression. Reply MouseDoctorFriday, February 19, 2016 1:03:00 pm I believe that you are right and the b cell and progression is part of a red herring. It is a hypothesis that b cells drive progression. There is no question of lesions on the surface of the brain and it is clear that antibodies in CSF can be damaging. The b cell follicles are debatable but people with Ms have oligoclonal b cell activation. Get rid of them and if MS goes away then QED. Likewise target innate inflammation and progression stops QED. However go about it half cocked and you end up with cock-up. Rituximab is never going to get at the plasma cells so it won't answer the question. 5 min of thought process rather than suck it and see. sometimes that works but generally it doesn't. Just because you can doesn't mean you should and if it puts the cause backwards then it is bad news. However Tally Ho is the clinical mantra maybe it is better to try and fail than not to try at all.