Optimal response to dimethyl fumarate is mediated by a reduction of Th1-like Th17 cells after 3months of treatment.

María José Mansilla,Cristina Ramo‐Tello,Silvia Presas‐Rodríguez,Aina Teniente‐Serra,Eva María Martínez‐Cáceres,Bibiana Quirant‐Sánchez,Juan Navarro‐Barriuso

doi:10.1111/cns.13142

Abstract

AimDimethyl fumarate (DMF) is one of the most promising therapies for relapsing‐remitting multiple sclerosis (RRMS) patients since it has shown immunomodulatory and neuroprotective effects. However, a percentage of RRMS patients do not exhibit an optimal response to DMF. The objective of this study was to identify early biomarkers of treatment response by analyzing changes in peripheral leukocyte subpopulations directly in whole blood samples.MethodsA longitudinal and prospective study analyzing peripheral blood leukocyte subpopulations in 22 RRMS patients before initiating DMF treatment (baseline) and at 1, 3, 6, and 12 months of follow‐up was performed. Differences between no evidence of disease activity (NEDA) and ongoing disease activity (ODA) patients were analyzed.ResultsThe beneficial effect of DMF was associated with a specific depletion of memory CD4+ and CD8+ T lymphocytes and B cells. Importantly, only NEDA patients showed (a) a shift from a pro‐ to an antiinflammatory profile, with an increase of Th2 cells and a decrease of Th1‐like Th17 lymphocytes; and (b) an increase of regulatory CD56bright NK cells.ConclusionThe optimal response to DMF is mediated by a shift to antiinflammatory and immunoregulatory profile, which puts forward Th1‐like Th17 lymphocytes as a potential early biomarker of treatment response.

Highlights

We identified that a reduction of effector memory Th1‐like Th17 cells is asso‐ ciated with increased Dimethyl fumarate (DMF) efficacy, which occurs already after 3 months of treatment in no evi‐ dence of disease activity (NEDA) patients and it is maintained until 12 months of treatment
Longi‐ tudinal studies are limited by the final number of patients completing the follow‐up period, but results obtained avoid interindividual vari‐ ability and are useful to monitor changes induced by the treatment over time
Our group has been collaborating in an international consortium to establish standardized multiparametric cytometric protocols to evaluate changes in leukocyte subpopula‐ tions of patients with autoimmune diseases such as type I diabetes, rheumatoid arthritis, or MS15,16 Importantly, these cytometric panels are performed on fresh whole blood samples, providing an easy, fast, and direct approach to obtain a readout of circulating leukocytes of patients able to be translated into clinical practice

Summary

Introduction

When the pro‐ and antiinflammatory effects of DMF were evalu‐ ated (Figure S2) by analyzing whole blood samples, a reduction of the Th1‐like Th17 population was found after 6 and/or 12 months of treatment in central memory and effector memory cells, respectively (P < 0.0001 in both subsets, Figure S3).

Objectives

Results

Conclusion