#ResearchSpeak & #CharcotProject: there are no original ideas

Why teriflunomide is a dark horse and may pack the killer punch. #ResearchSpeak #CharcotProject

Earlier this year I did a post on Teriflunomide being antiviral and many sceptics didn’t like the idea of it working as an anti-viral in MS. I am pleased to say that someone has now extended the antiviral effects of Teriflunomide to EBV. The study below includes one of the studies we were proposing to do. We simply did not get around to doing it quickly enough due to a current lack of funding and resources. Despite this it shows that Teriflunomide is a potent inhibitor of EBV infection in the laboratory and that it prevented EBV-induced lymphomas in an animal model. The next step is to look at what Teriflunomide does in pwMS in relation to EBV biology. Let’s hope our grant application that has been submitted gets funded so we can extend these observations into pwMS. 

What the study below shows is that there are no original ideas only people who act on their ideas. Could Teriflunomide be working as an antiviral in MS? Importantly, there is evidence that Teriflunomide penetrates the central nervous system (CNS) and therefore may be working with the brain and spinal cord of pwMS. 

It is a great pity that when you have an idea it takes months to years to get the work done. This is why science takes longer than you would like it to take. The only solution to this is to have a large discretionary pot of money to do blue sky projects of this nature or a science sugar mommy/daddy who is willing to fund such projects. 

I have little doubt that EBV is the cause of MS. What we now need to do is convince the wider community and use the information  to design trials to to treat and prevent MS based on this hypothesis. The latter is one of the arms of our new initiative called ‘Preventive Neurology‘. Could Teriflunomide provide us with a window to get there sooner? 

Bilger et al.  Leflunomide/teriflunomide inhibit Epstein-barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication.  Oncotarget. 2017 May 15. doi: 10.18632/oncotarget.17863.

Background: EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both “on target” and “off target” mechanisms and is increasingly used to treat these viruses in organ transplant recipients. 

Research question: However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. 

Results: We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. 

Conclusions: Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.

CoI: multiple

54 thoughts on “#ResearchSpeak & #CharcotProject: there are no original ideas”

  1. As it is often noted in medicine that a single observation does not change practice and it needs to be repeated (sometimes again and again). Apropos the need to observe the effect of teriflunomide in humans; this is now of paramount importance.

    1. "Apropos the need to observe the effect of teriflunomide in humans; this is now of paramount importance."Why not test a proper antiviral like famciclovir rather than Terileflunomide with questionable risk-benefit profile?

  2. you know, if the anti virals were the answer, i'd lose the little faith i have left in the ms community. and i don't really have that much left so that's a big statement lol

    1. It doesn't really matter it wasn't really our ideas either. We got the ideas underpinning this in parallel from Keith Edwards and Genzyme scientists, who in turn got the ideas from other people working on leflunomide. It is not important who's idea it is, it is more important translate the ideas.

    2. P.S. if this is the answer we have to explain why it is not a more highly active drug or is it it is not a very good anti viral. Eg beta interferon is anti viral.

    3. "It is not important who's idea it is, it is more important translate the ideas.""That's why we do grant idea of the month where we give ideas here for free"If your post docs or other juniors have an idea, work on grant proposals etc, should they expect their ideas to be discussed before funding decision have been made? What about their REF returns?

    4. The juniors are not REF returned and I do not talk about their ideas,and if you do not get it this is a bit tounge in cheek but we are giving ideas away

    5. "I have little doubt that EBV is the cause of MS"What do we make of this them?The presence of Epstein-Barr Virus (EBV) DNA in cerebrospinal fluid (CSF) and peripheral blood (PB) samples collected from55 patients with clinical and radiologically-active relapsing-remitting MS (RRMS) and 51 subjects with other neurologicaldiseases was determined using standardized commercially available kits for viral nucleic acid extraction and quantitativeEBV DNA detection. Both cell-free and cell-associated CSF and PB fractions were analyzed, to distinguish latent from lyticEBV infection. EBV DNA was detected in 5.5% and 18.2% of cell-free and cell-associated CSF fractions of patients with RRMSas compared to 7.8% and 7.8% of controls; plasma and peripheral blood mononuclear cells (PBMC) positivity rates were7.3% and 47.3% versus 5.8% and 31.4%, respectively. No significant difference in median EBV viral loads of positive sampleswas found between RRMS and control patients in all tested samples. Absence of statistically significant differences in EBVpositivity rates between RRMS and control patients, despite the use of highly sensitive standardized methods, points to thelack of association between EBV and MS disease activityhttps://www.researchgate.net/publication/261603389_Quantitative_Detection_of_Epstein-Barr_Virus_DNA_in_Cerebrospinal_Fluid_and_Blood_Samples_of_Patients_with_Relapsing-Remitting_Multiple_Sclerosis

    1. Yes, EBV causes several types of cancer. Lymphomas (Burkitt's Hodgkin's and other B-cell lymphomas), nasopharyngeal carcinoma and some gastric carcinomas and EBV has been linked to several other cancer related complications. The NIH investment in an EBV vaccine is driven by onco-prevention rather than preventing MS and other autoimmune diseases.

    2. Somebody told me there is a benefit having EBV otherwise we wouldn't have over 90% of the population carrying the virus. Is there any evidence for detrimental effects when you are EBV negative?

    3. Thanks… Good to know. It's awesome to get lateral research from the cancer funding pot.

    4. There does not have to be any benefit of EBV just because a lot of the population is infected. It is that it does not do enough damage before people have had children to drive any evolutionary change. It is rather good at not killing or maiming MOST people. It causes Mixed Cellularity Hogkins Lympohoma, and my money is on it cause Chronic Fatigue. (ME).

    5. "Somebody told me there is a benefit having EBV otherwise we wouldn't have over 90% of the population carrying the virus."A virus which doesn't kill its host has more evolutionary advantage in terms of opportunity to be passed on. There is no evolutionary drive for a virus to kill its host. So the common cold is a lot more "successful", i.e. widespread than Ebola or bubonic plague. That EBV is so widespread is a result of not (or no longer) being fatal in the shorter term at least. Perhaps early forms/strains of EBV were deadly earlier on within their host. Such forms would have been at a selective disadvantage.

    6. RE: "Somebody told me there is a benefit having EBV …"Likely this blog. I hypothesised several years ago that because EBV is so ubiquitous it obviously co-evolved with humans and may therefore play a positive role in our biology. Therefore eliminating EBV from our meta-genomes (human DNA + the microbiome) may have long-term consequences at a population level. Although it may have positive effects at a population level does not stop it have negative or deleterious effects at an individual level.

    7. I didn't find no benefit so far from EBV in the scientific literature, on the contrary, it's the major cause of infectious mononucleosis in children and adults, and its infection endures in the body and may be triggering other diseases depending on "circumstances", which may be genetic, or other environmental factors, etc., found in the host.

    8. H'mm, not sure evolution is interested in us once we've raised our children. In fact, horrible thought, probably an advantage in evolutionary terms in us not living too long.

    9. It's true MD, may be a positive function of EBV. But at the same time EBV is linked to so many diseases…

    10. "H'mm, not sure evolution is interested in us once we've raised our children. In fact, horrible thought, probably an advantage in evolutionary terms in us not living too long."If you look at orcas, killer whales, there is strong evidence to show that pods benefit from the presence of older individuals' experience. They are an unusual species, in that they exhibit menopause, like humans. Survival well beyond reproductive age supports the idea that knowledge gained over many years benefits a pod's survival. There are also observations of orcas supporting injured, disabled individuals which are no longer able to catch food themselves.EBV evolution loses its driver once infected individuals survive to reproduce. Maybe EBV was once much more deadly. It still merits annihilation I think. We can send probes beyond the solar system, sending back data as they go. But we still know **** all about MS. In my view, as a PPMSer.

  3. "I have little doubt that EBV is the cause of MS. What we now need to do is convince the wider community and use the information  to design trials to to treat and prevent MS based on this hypothesis. The latter is one of the arms of our new initiative called 'Prevent Neurology'. Could Teriflunomide provide us with a window to get there sooner?" End Quote Could artesunate accomplish much the same with better safety and fewer side effects? Artesunate appears to have some good effect against EBV and other herpes viruses. Also has some effect against Polyomavirus BK replication. All in all, it has made artesunate a candidate for consideration in this household when transitioning off of natalizumab onto ocrelizumab. Perhaps, artesunate may be effective on its own in thwarting MS by its action on viruses thought by some to be at the root of MS.

    1. Re atesunateSensitivity of human herpesvirus 6 and other human herpesviruses to the broad-spectrum antiinfective drug artesunate.Milbradt J, Auerochs S, Korn K, Marschall M.J Clin Virol. 2009 Sep;46(1):24-8. Artesunate Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Leukocyte Migration to the Central Nervous System.Thomé R, de Carvalho AC, Alves da Costa T, Ishikawa LL, Fraga-Silva TF, Sartori A, de Oliveira AL, Verinaud L.CNS Neurosci Ther. 2016 Aug;22(8):707-14. The problem it has never been into MS. Teri is a licensed MS DMT.

    2. It is quite intriguing that teriflunomide may help treat and/or help prevent MS because of its anti-viral activity. Further study certainly is warranted and those with MS along with caregivers are very supportive of efforts to do so. Hopefully, some young researcher will be intrigued enough by artesunate to study it relative to MS.I am personally thankful for the men and women who have dedicated so much of their lives for the benefit of pwMS. There are patients and caregivers whose appreciation more often finds expression in private tears of gratitude rather than in public acknowledgement of those who labor on their behalf.There is a noble grace, an incomparable grace, exhibited by those of you who spend yourself for others who have no way of repaying your efforts. You can be sure that if there is a God interested in the affairs of man your efforts do not go unnoticed by such. And if you believe there is no God in heaven then may our affection and appreciation be the reward which warms your heart in the knowledge you have chosen your vocation wisely to the good of those less fortunate and less capable of effecting humanity as positively as you do.If you were paid by esteem you would be extremely wealthy. This blog is making an important difference in the lives of a lot of people. Knowledge, and the application of it, is a healing balm.

  4. EBV is well documented as causing meningitis with encephalitis in man, though chiefly in children. It is also occasionally associated with ADEM, transverse myelitis, and radiculopathy. Outcomes of the active presence of the virus in the CNS are variable, from death to total recovery. Neurological complications occur in about 15% of IM cases Pathologically the virus has a definite tropism for the basal ganglia. Is there any evidence that the definite pathological presence of the virus in the human CNS causes, even as a sequel, a demyelination at all similar to MS? What is going on? Is There is a need for some discussion on this? The paper published in 2017 by the GG team 'EBV negative MS: a true phenomenon?' has had scant discussion. Quote, 'it is possible to be truly EBV seronegative and develop MS' which seems pertinent to the EBV question. The problem with this paper in which the authors nearly rupture themselves to produce antibody to EBNA 1 in routinely seronegative patients, is the the positive cases dug out of this group by 'more sensitive tests', are not adequately controlled. Sera from other neurological diseases that are EBV negative should have been similarly analysed.Any comments?

  5. My next door neighbours developed lymphoma. She's fine now, but I wonder if I shed EBV? I think I may. Oh, the guilt. Please take it away?

    1. You will shed Epstein Barr virus no more than any other person in the population that carries the virus (about 90%) and there are many other triggers for lymphoma. There is no guilt.

  6. I loved this post!An unexplained aspect is that missing the link between EBV and MS is to translate the position that women are more affected by the disease than men, and why when men are affected, MS tends to be more aggressive. Achieving to demonstrate that there are differences between the viral manifestation depending on the hormones and the gender (through genetic factors) will be very important. Oncology has a lot to collaborate with Neurology and contrariwise.

  7. I don't get your way of thinking. You have an already known mode of action for teriflunomide, similar to other MS drugs that hit the immune system: "…inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation."So, teriflunomide leads to less available T-cells, something that is regarded as the fundamental acting pathway of Tysabri and Gilenya. And yet, you prefer to bet on its antiviral properties and thus contradict your own arguments in favor of the drugs above.If teriflunomide acts as antiviral, while reducing T-cells, then what is the mechanism of action of other drugs that reduce T-cells too?Last, if EBV is the cause of MS, why doesn't it erupt within the CNS as JC virus does in Tysabri treated patients? After all, it is in there right from the beginning in the majority of patients.

  8. You may be interested in this article here, as well as Team G:Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawalBarbara SerafiniEmail the author Barbara Serafini, Eleonora ScorsiEmail the author Eleonora Scorsi, Barbara RosicarelliEmail the author Barbara Rosicarelli, Valérie RigauEmail the author Valérie Rigau, Eric ThouvenotEmail the author Eric Thouvenot, Francesca Aloisi'Correspondence information about the author Francesca AloisiEmail the author Francesca AloisiAbstractRebound of disease activity in multiple sclerosis patients after natalizumab withdrawal is an potentially life-threatening event. To verify if highly destructive inflammation after natalizumab withdrawal is associated with Epstein-Barr virus (EBV) reactivation in central nervous system infiltrating B-lineage cells and cytotoxic immunity, we analyzed post-mortem brain tissue from a patient who died during fulminating MS relapse Following natalizumab withdrawal. Numerous EBV infected B cells / plasma cells and CD8 + T cells infiltrated all white matter lesions; The highest frequency of EBV lytically infected cells and granzyme B + CD8 + T cells were observed in actively demyelinating lesions. These results may encourage switching to B-cell depleting therapy after natalizumab discontinuation.http://www.jni-journal.com/article/S0165-5728(17)30055-3/abstract

    1. Hi again Cinara 1.51I'm getting a sense of deja vu reading this abstract, has it been posted here very recently? Those exhausted, old CD8 are doing their best to tackle the exploding virus factory in all those mem B. Hope all the MS charities are keeping up with ebv research news…

    2. Hi, Judy. Yes, I posted it again in the space for "Unrelated Blogger Comments" for the month of June. I did this to emphasize the publication, to see if anyone on Team G sees and comments on it.

    3. The article describes a rebound effect, not an EBV infection.EBV is supposed to be in the CNS of most patients, since it resides in B cells and they enter CNS as part of MS process. So, one would expect that Tysabri normal use, not withdrawal, would let EBV flourish, just like JC virus does, once it gets inside CNS. Yet, nothing like this happens.

  9. I really like to know just one thing :If teriflunomide atacks Ebv and Ebv is the cause of Ms why is there 30% response only?Sure if you would clean all those Ebv from the system you should at least get an greater % response from patiensThankLuis

    1. The only know cases of EBV being cleared from a person are after a full stem cell transplant. The drugs damp it down they do not remove it. Also it may not be the virus acting directly that causes MS. The virus damages and immortalises B cells and it may be a sub set of these cells that cause MS, because of the damage.

    2. Still, MS remains even after full stem cell transplant.EBV has been chosen as a candidate in order to account for the relapse-remmission phenomena of MS. Passing the damaging role to some mysterious B cell subset, leaves these phenomena largely unanswered. Why do these B-cells begin to act (relapse)? Why do they stop (remission)? How and why do the create Dawson's fingers?

    3. "EBV has been chosen as a candidate in order to account for the relapse-remmission phenomena of MS."Not only ms but a host of autoimmune disease. EBV isfound in the target organ..brain for MS..joints for RAhttps://www.hindawi.com/journals/jir/2013/535738/"This review focuses on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren’s syndrome (SS) and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities.."

    4. For the action of triggering MS on the part of the EBV need "favorable" genetic factors for it, ie the virus will interact with alleles such as HLA DRB 1*15 and trigger the series of events you described yourself.HLA-DRB1 15:01 and Epstein-Barr virus in a multiple sclerosis patient with psoriasis, nasopharyngeal and breast cancers. Lessons for possible hidden links for autoimmunity and cancer.Anagnostouli M1, Anagnostoulis G2, Katsavos S3, Panagiotou M4, Kararizou E4, Davaki P4.AbstractBACKGROUND:Multiple sclerosis (MS) patients have a low general cancer risk and cases of neoplastic comorbidity are attributed by many researchers in chance, or therapeutical side-effects. Human leucocyte antigen (HLA) class II allele DRB1 15:01 is considered the main genetic factor independently associated with increased susceptibility for MS in Caucasians. Epstein-Barr virus (EBV) has also been proven to be a core triggering factor in MS initiation and progress, mainly in HLA-DRB1 15:01 positive MS patients.CASE REPORT:We present an exceptional case of a Greek-origin woman, carrying a distinct immunogenetic profile (HLA-A 26:01-Cw 06:02-DRB1 15:01), which gradually developed psoriasis, nasopharyngeal carcinoma (NPC), MS, breast cancer, uterine leiomyoma and other neoplasms.DISCUSSION:EBV plays a fundamental role in the pathogenesis of both autoimmunity (i.e. MS) and cancer (i.e. NPC). Our patient's immunogenetic profile included HLA alleles which are associated with psoriasis (Cw 06:02), NPC (A 26:01), MS (DRB1 15:01) and increased risk of MS, in patients carrying EBV (DRB1 15:01). We made a targeted review of the literature finding data supporting an EBV-HLA interaction mechanism behind our patient's unique combination of disorders, suggesting that beyond the standard role of each factor, their combination could act as the hidden link, in initiation or/and comorbidity of autoimmunity and cancer.https://www.ncbi.nlm.nih.gov/pubmed/24576802See this other link here, the text is huge: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676020/

    5. Interesting the association between HLA-DR 1 genotype and EBV. via dysregulation of thymic negative selection and molecular mimicry with CNS Ag(s). Maybe MD knows if there are any studies on the binding affinity of EBNA 1 and the MHC II complex that would prevent T cells from becoming activated and leaving the thymus. Also, has there been any homology comparisons between EBNA peptides and possible CNS peptides that would lead to cross reaction and damage in the CNS. Thanks for the paper Cinara, interesting.

    6. "Still, MS remains even after full stem cell transplant." According to papers reported on this very blog MS can be treated very well with stem cell transplants. The damage remains but the disease stops. "EBV has been chosen as a candidate in order to account for the relapse-remmission phenomena of MS. Passing the damaging role to some mysterious B cell subset, leaves these phenomena largely unanswered. " They are not mysterious they are cells damaged by the EBV virus, they are immortalised by the virus and their behaviour and structure is modified. The difference is that it is the cells that orchestrate the immune attack and not the virus directly, so you don't detect an increase in the virus locally. The cells however are infected and will respond to the virus they still contain. If you wish to see how a few damaged B cells can cause large changes in the immune system go study mixed cellularity Hodgkin's Lymphoma. This disease causes effects in parts of the body where the lymphoma is not present. The lymphoma is also made up of very few cancer cells surrounded by vast numbers of other immune cells. This shows the level of distribution a few of these cells can cause.

    7. "Not only ms but a host of autoimmune disease. EBV isfound in the target organ..brain for MS..joints for RA"MS is of unknown aetiology, and certainly not autoimmune against myelin. EBV is found is CNS because it resides in B cells, and B cells take part in the CNS inflammation. There is no proof of EBV acting causally in MS. The relevant arguments are only statistical."the virus will interact with alleles such as HLA DRB 1*15 and trigger the series of events you described yourself."Please provide proof. Also, please explain relapse, remission, MS lesion topology through this interaction. The Greek paper considers MS autoimmune already, they live in a Prineas-free universe. The Chinese paper is a meta research. Sorry, statistics can't describe pathogenetic mechanisms."The difference is that it is the cells that orchestrate the immune attack and not the virus directly"Surely, not against myelin. Then against what? Any proof? May I remind you of another Prineas paper about brain damage taking place BEFORE any immune cell infiltration?Multiple sclerosis: distribution of inflammatory cells in newly forming lesions.https://www.ncbi.nlm.nih.gov/pubmed/20035511This is hard anatomy data on real patients. Not statistical, not on rodents. How can you fit the EBV-immortalised-B-cell-autoimmunity into this?

    8. I dont have acess to the full paper but from the abstract they suggest that the plaques are already there when the adptative immune system ( b and t cell) arrive and they arrive to repair oligodendrocytes ?Thanks Luis

    9. Vasilis Vasilopoulos: These are ideas not facts, they are ways of trying to move concepts forward so they can be tested. For decades research in MS has not got very far, which tends to insinuate we are thinking about it wrong. All that works are drugs that take a blunderbuss to the immune system. The indication that mutated B cells can interact with the nervous system is from the intense and severe itching that occurs in some with Hodgkin's Lymphoma. It occurs sometimes years before there is an observable lymphoma, and we do not have a mechanism for how it occurs. It is not the same but shows there is a possibility that might as well be checked out.

    10. The other point to consider is if it is damaged immortalised B cells rather than the virus acting directly then antivirals may not work, you may have to kill the cells, not the virus.

    11. @Luis:"An important new observation related to myelin destruction in rapidly evolving lesions was the unexpected finding that lymphocytes were present in very small numbers, not only in prephagocytic areas but also in adjacent areas of commencing myelin phagocytosis.Rather than an influx of T cells, the dominant inflammatory infiltrate in this region of the plaque was composed of large numbers of MRP-14 –positive proliferating monocytes in the Virchow Robin spaces of small blood vessels and in surrounding tissues, an event that coincided with transformation of IgG-negative ramified microglia into IgG-positive macrophages. There is evidence that MRP14-positive monocytes and macrophages in MS lesions are recruited from a pool of circulating monocytes that express the chemokine receptors CCR1 and CCR546,47 in response to chemokines and cytokines that specifically attract monocytes and that are expressed by glia in MS lesions.""These observations, and the fact that myelin sheaths throughout such areas are detached from viable oligodendrocytes, suggest that innate macrophage scavenger activity, rather than typical T-cell–mediated macrophage activation, underpins macrophage-myelin engagement in MS. Consistent with this are reports describing active myelin phagocytosis in MS lesions with few T cells and absent B cells and plasma cells in patients who have received intense immunosuppressive treatment. Thus, myelin phagocytosis in MS appears to be an innate immune response directed at degenerate myelin, similar to that seen in traumatic and ischemic lesions where a rapid influx of monocytes and transformation of ramified microglia result in rapid removal of degenerate tissue. However, in contrast to the conditions mentioned, monocyte infiltration in MS is not accompanied by an initial influx of granulocytes."

  10. Aubagio is a weak second line MS drug that does not work very well in terms of either reducing relapses or disability, almost equivalent to a CRAB drug in terms of efficacy and just barely above placebo (see TEMSO and TOWER trials). If your hypothesis, Dr. G, is that these EBV-controlled memory B-cells in the follicles of the brain are responsible for relapses and progression of MS, should Aubagio not have had better results on MS relapses and progression? Why does Aubagio have such pathetic results if it is a potent inhibitor of EBV, which you believe is the root cause of MS? Just wondering.

    1. Guessing Nissan 3.24 and Luis 3.17 teri is only a weak antiviral. Roll on Charcot!

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