Is DMF the new GA?

I

Glatiramer acetate has had more mechansims than most people have had hot dinners :-), without really asking the question how it works but does it work well enough? However, is dimethyl fumarate DMF moving in the same territory.

Dimethyl fumarate was first described to be an anti-oxidant working via Nrf2. Work in Nrf2 knockout questioned this and then we had GPR105 and a CD8 dependent mechanisms and then there is the B cell dependent mechanism possiblity, now its the monocycte. Flip Flop, Flip Flop.

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes.Carlström KE, Ewing E, Granqvist M, Gyllenberg A, Aeinehband S, Enoksson SL, Checa A, Badam TVS, Huang J, Gomez-Cabrero D, Gustafsson M, Al Nimer F, Wheelock CE, Kockum I, Olsson T, Jagodic M, Piehl F. Nat Commun. 2019 ;10(1):3081.

Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.

Don’t believe me a quick look at papers this week suggest it is acting on CD4 T cells

Th1Th17CM Lymphocyte Subpopulation as a Predictive Biomarker of Disease Activity in Multiple Sclerosis Patients under Dimethyl Fumarate or Fingolimod Treatment.

Quirant-Sánchez B, Presas-Rodriguez S, Mansilla MJ, Teniente-Serra A, Hervás-García JV, Brieva L, Moral-Torres E, Cano A, Munteis E, Navarro-Barriuso J, Martínez-Cáceres EM, Ramo-Tello C. Mediators Inflamm. 2019 Jun 26;2019:8147803

Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in peripheral blood samples from 66 RRMS patients under DMF (n = 22) or fingolimod (n = 44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1CM cells (central memory) (relapsed: 11.60 ± 4.17%vs. nonrelapsed: 9.25 ± 3.17%, p < 0.05) and Th1Th17CM cells (relapsed: 15.65 ± 6.15%vs. nonrelapsed: 10.14 ± 4.05%, p < 0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17CM (CD4+CCR7+CD45RACCR6+CXCR3+) cells > 11.48% had a 50% relapse-free survival compared to patients with Th1Th17CMcells < 11.48% whose relapse-free survival was 88% (p = 0.013, log-rank test). Additionally, a high percentage of Th1Th17CM cells was also found in patients with MRI activity (MRI activity: 14.02 ± 5.87%vs. no MRI activity: 9.82 ± 4.06%, p < 0.01). Our results suggest that the percentage of Th1Th17CM lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.

Thus Th1Th17 (Based on chemokine receptor expression are the important type. Fingolimod blocks central memory cells and keeps them in the lymphoid tissue. However, if we look in the brain of MS, it is the effector memory note the central memory that accumulates in the brain. However, it shows that many things are changing and you need to know where to look to determine what is the important subsets that changes.

About the author

MouseDoctor

1 comment

  • COI:

    by an unrestricted academic research grant from Biogen, Hjärnfonden, NEURO Förbundet

    T.O. has received unrestricted MS research grants, and/or lecture advisory board honoraria from Biogen, Novartis, Sanofi and Roche.

    Flip;;;;;$$$$$

    Flop;;;;;;€€€€€

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives