Dimethyl fumarate as a first- vs second-line therapy in MS

Abstract

ObjectiveTo elucidate the immunomodulatory effects of dimethyl fumarate (DMF) on B cells in patients with relapsing MS receiving DMF as a “1st-line” vs “2nd-line” therapy.MethodsB cells were isolated from 43 patients with MS at baseline and after 15-week DMF therapy. Phenotype and functional markers and cytokine profile were assessed by flow cytometry. Analysis included clinical and MRI parameters recorded during a 1-year follow-up.Results1st-line and 2nd-line patients presented several differences in their baseline immune profile, which corresponded with differences in their immunologic response to DMF treatment. DMF reduced the proportions of B cells and CD8 T cells whereas increased monocytes. DMF reduced memory B cells, including plasma cells in 2nd-line patients only, whereas strongly increased transitional B cells. Several IL10+ B-cell subsets and TGFβ+ B cells were increased. Proinflammatory LTα+ and TNFα+ B cells were reduced, while IL4+ B cells elevated, whereas IFNγ+ B cells showed opposite effects in 1st-line and 2nd-line patients. HLA and ICAM-1 expression was increased, but % CD86+ B cells reduced. The expression of B-cell activating factor receptor and the proportion of activated CD69 B cells were increased.ConclusionsDMF is associated with increased transitional and IL10+ and TGFβ+ regulatory B cells and a shift toward a more anti-inflammatory immune profile. Cell activation with reduced costimulatory capacity may induce immune hyporesponsiveness. Carryover effects of preceding therapies in 2nd-line patients and the stage of disease influence the immune profile of the patients and the immunomodulatory effects of DMF.

Impact of treatment on cellular immunophenotype in MS

“…9,27,28,36 Other DMTs had an impact on immune cell profile. Thus, as already reported, CD8 + T cells 31,37 and B-reg and B-memory cells 11,25 were affected by DMF treatment. The limited use, in our cohort of patients, of DMTs that more recently entered the market in Europe did not allow us to obtain enough information on B cell-depleting agents and on cladribine.…”

“…Altered levels and/or functional abnormalities in T or B cells have already been reported in patients with MS. 12,[19][20][21] However, previous studies are generally characterized by several limitations, including the focus on particular restricted immune cell subsets, small groups of patients mainly treated with a single DMT, 11,[22][23][24][25][26][27][28][29][30][31] different disease characteristics, lack of inclusion of controls, and difficult standardization of sample processing. 5,13,15,16 In this study, we have undertaken a large multicentric analysis of the immunologic profile of T and B cells in a cohort of 227 patients with MS at different disease stages treated with different DMTs and 82 HCs.…”

“…[3][4][5][6] Changes in immune cell subsets in peripheral blood mononuclear cells (PBMCs) have been proposed as surrogate biomarkers of activity to monitor treatment response in MS and help in treatment decision. [7][8][9] Immunophenotyping studies of patients with MS have focused on alterations in composition and function of T-or B-cell subsets, [10][11][12] but comprehensive studies are lacking and present discrepancies. 13 Although a few studies comparing the effect of different disease-modifying treatments (DMTs) on immune cells are available, reproducibility of reliable findings is lacking, possibly due to technical issues including the use of different flow cytometry parameters and monoclonal antibodies defining cell subpopulations.…”

CD4+CD62L+ cells: A monitoring marker of fingolimod dosage in multiple sclerosis

“…25 Most patients with FTY-PML were treated with FTY for >2 years and did not report severe lymphocytopenia. 27,28 The pharmacological effects of DMF are different from FTY, and it is no wonder that the decreased number of CD4/62L cells will not be a biomarker of the beneficial effects of DMF. Most lymphocytes causing inflammation in the central nervous system of patients with MS were included in the CD4/62L cell fraction.…”

“…15 It was also reported that the CD4/62L cell population was increased in patients treated with DMF by inducing the nuclear factor (erythroidderived 2)-related factor 2 pathway, which downregulates the nuclear factor-jB pathway. 27,28 The pharmacological effects of DMF are different from FTY, and it is no wonder that the decreased number of CD4/62L cells will not be a biomarker of the beneficial effects of DMF. In addition, the function of CD4/62L cells, including eliminating the John Cunningham virus, remains only partially understood; however, gradual intermittent drug holidays with CD4/62L cells used as a biomarker are useful to prevent excessive FTY administration or disease relapse.…”