Teriflunomide affects T cells…But with Alem its all Magic

T

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects.Klotz L, Eschborn M, Lindner M, Liebmann M, Herold M, Janoschka C, Torres Garrido B, Schulte-Mecklenbeck A, Gross CC, Breuer J, Hundehege P, Posevitz V, Pignolet B, Nebel G, Glander S, Freise N, Austermann J, Wirth T, Campbell GR, Schneider-Hohendorf T, Eveslage M, Brassat D, Schwab N, Loser K, Roth J, Busch KB, Stoll M, Mahad DJ, Meuth SG, Turner T, Bar-Or A, Wiendl H. Sci Transl Med. 2019;11(490)

Interference with immune cell proliferation represents a successful treatment strategy in T cell-mediated autoimmune diseases (So leading voices including a major B cell therapy investigator (Bar-Or) say it is all about T cells. I guess this view explains why it is difficult to have any other views as T cells are not top of the pile). such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. (Hardly prominent …as teriflunomide is considered to be a low efficacy agent) Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells (Yep EAE is CD4 T cell mediated..we are all agreed on this) . Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment . Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity.

They say “Teriflunomide tampers with T cells

“Activated T cells need de novo pyrimidine biosynthesis, which has been exploited for autoimmune therapy. Klotz et al. studied samples from patients with multiple sclerosis treated with the dihydroorotate dehydrogenase inhibitor teriflunomide. They found that teriflunomide did not affect all T cells equally and led to repertoire and subset distribution changes. They also used a mouse model of T cells with higher and lower affinity for the same antigen to explore the drug’s effects. Collectively, their data demonstrate that high-affinity T cells preferentially use mitochondrial respiration, which is then inhibited by teriflunomide”.

So highly activated cells that will be responding get killed. Here they find that TH17 and TH2 cells are not affected but TH1 get affected and the repetorie is not uniformally affected, but why would it be if only proliferating cells are affected. Does this explain the lack of efficacy, as its not Th17?.

I am not going to try do this justice to this, so will let you read it for yourself, but they can’t be bothered to even look at the B cells so have they missed something? They are not effected that much by teriflunomide but hey I suppose Teri is not that effective in MS based on inhibition of relapse rate….it is T cells, T cells. Let’s not try to show otherwise.

AAN2019 Alemtuzumab its all magic

AAN20019. Alemtuzumab its all Magic

So back to the AAN and the same people above look at the influence of alemtuzumab and T and B cell subsets and disease activity and we must conclude it is all magic.

No Association Between Lymphocyte Pharmacodynamics and Disability Following Alemtuzumab Treatment in Patients With Relapsing-Remitting Multiple Sclerosis Sven G Meuth , David Brandes , Matthew Carraro , Giancarlo Comi , Yang Mao-Draayer , Guillermo Izquierdo , Ho Jin Kim , Gabriel Pardo , Basil Sharrack , Carlo Tornatore, Bart Van Wijmeersch, Tjalf Ziemssen, Alan Jacobs, Luke Chung, Nadia Daizadeh, Heinz Wiendl

Objective: Compare lymphocyte pharmacodynamics over 2 years in alemtuzumab-treated relapsing-remitting MS (RRMS) patients with improved, worsened, or stable disability through 6 years. Background: In the phase 3 CARE-MS studies (NCT00530348; NCT00548405), alemtuzumab 12 mg/day (baseline: 5 days; 12 months later: 3 days) significantly improved clinical/MRI outcomes versus subcutaneous IFNB-1a over 2 years in patients with active RRMS. Efficacy was maintained in a 4-year extension (NCT00930553) without continuous treatment; 53% of patients received no additional alemtuzumab or other disease-modifying therapy. The effects of alemtuzumab over time may be due to its selective depletion and distinctive repopulation of circulating CD52-expressing T and B lymphocytes. Design/Methods: Blood counts were obtained monthly; lymphocytes were phenotyped by flow cytometry quarterly and at Months 1 and 13 (1 month after alemtuzumab Courses 1 and 2, respectively). Pharmacodynamic assessments (using pooled CARE-MS data [n=802]) included: total counts of lymphocytes, CD3+ /CD4+ /CD8+ T cells, and CD19+ B cells; CD4+ /CD8+ naive/memory/regulatory (Treg); and CD19+ immature/mature/memory. Ratios of CD19+ B cells (total/immature/memory) to CD4+ and CD8+ Treg cell counts were also assessed. Relationship between lymphocyte repopulation patterns and disability was assessed in patients with 6-month confirmed disability worsening (CDW; ≥1.0-point Expanded Disability Status Scale [EDSS] increase [≥1.5 points if baseline EDSS=0]), 6-month confirmed disability improvement (CDI; ≥1.0-point EDSS decrease from baseline

[assessed in

), or stable EDSS (neither CDW nor CDI). Results: No significant overall difference in lymphocyte depletion or repopulation patterns was observed over 2 years in patients who experienced CDI, CDW, or neither through 6 years. No correlation was observed between CDI, CDW, or stable EDSS and any CD19+ /Treg ratio.

Conclusions: Differences in depletion and repopulation kinetics of the tested lymphocyte populations in the first 2 years after initiating alemtuzumab did not appear to be associated with improved, worsening, or stable disability in RRMS patients.

So whilst you can make a story of looking at the bloods (above Top) of a weakly active drugs, looking at the bloods with a highly active drug (above bottom) you can’t…it must work by magic. Therefore, these are two related studies in a way, but do they get seen as anything but binary (this one and that one) I doubt it. This maybe is why I get chastised by the reviewers (some I suspect in the list above:-(, for spectulating when I try and relate different bits of information together.

You write a paper and forget all else that is around it. What a terrible way to do science, but the blinkers are on, so when I see the introductory comment in a paper…this is the first….or the blah blah is unknown..so we can justify the work. I cringe. Then I do some reading and see invariably not the first so I then hope the work is not done like their capacity to do a literature review. It is infact a sad way of making work seem important when it probably is not.

You can’t look at the blood and see anything useful that correlates with disease activity. This means nothing in the T cell subsets and nothing in the B cell subsets

This blows my idea of memory B cells being important in MS away?

Now I have no problem with this as we know you can relapse without peripheral B cells being detected and so the blood is probably only a conduit for the important stuff being done elsewhere.

Two years ago I asked the manufacturers to give us the data between alemtuzumab depletion and repopulation and the imaging and relapse rates…No way are we getting the data. The company go off for five months and come back and present data on why they think T reg numbers are not associated with autoimmunity and just say to ProfG there is no difference.

They never show the data, but now we see this. There is no relation ship to depletion of T or B cells and progression. The T cells stuff is lumped with the B cell stuff and it is magic so must be T & B cell balance.

However, why look at this outcome, as disability progression is a composite of relapses/lesion acquistion which responses to such DMT and progression which we know responds poorly. But why look what happens in the bloods now and relate it to five years away. This is the stuff of MRI which leads to the the usual population based correlation that has little predictive value for the individual. If the effects in the blood are to be considered useful the question is what happens in the months before the relapse/lesion.

You have to interrogate the data there may be gold dust in there That is the analysis I would like to see. Go on put me out of my misery, you can even put a football team of authors on the abstract You have a large data set. Pre-empt all thse papers that will come down the line doing just this and then you can do it for the first time with alemtuzumab. But if all you think about is T cells….Em

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  • Another on Teri and its effect on PBVC

    Brain Volume Loss and Cognition in Teriflunomide-Treated Patients in TEMSO
    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-003039.pdf

    Results:Teriflunomide 14 mg reduced the decline in cognition (LS mean difference [SE] compared with placebo = 0.113 [0.046]; P=0.0146). Teriflunomide 14 mg reduced the number of active T2w lesions by 52% (P<0.0001), total number of relapses by 62% (P=0.0004), and PBVC by 0.461% (P=0.0008) compared with placebo. PBVC demonstrated the strongest utility as a surrogate, accounting for 44.3% of teriflunomide’s effect on cognitive impairment, followed by active T2w lesions (16.8%) and relapses (7.1%). Combined, the three surrogates explained no more of the treatment effect on cognition than PBVC alone.
    Conclusions: Teriflunomide’s effect on cognition (PASAT-3 performance) may be mediated, in part, by its effects on PBVC, suggesting that teriflunomide impacts neurodegenerative aspects of MS

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