Effect of dimethyl fumarate on lymphocytes in RRMS

Abstract

ObjectiveTo assess functional changes in lymphocyte repertoire and subsequent clinical implications during delayed-release dimethyl fumarate (DMF) treatment in patients with multiple sclerosis.MethodsUsing peripheral blood from several clinical trials of DMF, immune cell subsets were quantified using flow cytometry. For some patients, lymphocyte counts were assessed after DMF discontinuation. Incidence of adverse events, including serious and opportunistic infections, was assessed.ResultsIn DMF-treated patients, absolute lymphocyte counts (ALCs) demonstrated a pattern of decline followed by stabilization, which also was reflected in the global reduction in numbers of circulating functional lymphocyte subsets. The relative frequencies of circulating memory T- and B-cell populations declined and naive cells increased. No increased incidence of serious infection or malignancy was observed for patients treated with DMF, even when stratified by ALC or T-cell subset frequencies. For patients who discontinued DMF due to lymphopenia, ALCs increased after DMF discontinuation; recovery time varied by ALC level at discontinuation. T-cell subsets closely correlated with ALCs in both longitudinal and cross-sectional analyses.ConclusionsDMF shifted the immunophenotype of circulating lymphocyte subsets. ALCs were closely correlated with CD4+ and CD8+ T-cell counts, indicating that lymphocyte subset monitoring is not required for safety vigilance. No increased risk of serious infection was observed in patients with low T-cell subset counts. Monitoring ALC remains the most effective way of identifying patients at risk of subsequently developing prolonged moderate to severe lymphopenia, a risk factor for progressive multifocal leukoencephalopathy in DMF-treated patients.Trial registration numbersEUDRA CT 2015-001973-42, NCT00168701, NCT00420212, NCT00451451, and NCT00835770.

Differential effects of disease modifying drugs on peripheral blood B cell subsets: A cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab

“…Concerning DMF, we found an increased percentage in naïve B cells along with a relative reduction of memory B cells which is in line with the literature [22,28]. Absolute counts of double negative B cells were significantly decreased while memory B cells also showed a trend towards reduced numbers.…”

Diroximel fumarate (DRF) in patients with relapsing–remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study

“…However, thus far there have been no unexpected safety or efficacy findings with DRF compared with the 2-year clinical trial DMF experience, which has been consistent in long-term (up to 12 years' exposure) extension studies and realworld experience. [2][3][4]6,20 Conclusion DRF is a novel oral fumarate with a distinct chemical structure in development for patients with RRMS.…”

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

“…Dimethyl fumarate is modestly immunosuppressive and targets lymphocytes rather than monocytes (Pardo and Jones 2017;Diebold et al, 2018). Immature/transitional B cells are less affected compared to memory B cell targeting (Mehta et al, 2019). Although plasmablasts and plasma cells can be affected by dimethyl fumarate therapy (Mehta et al, 2019), immunoglobulin levels are not unduly reduced (Diebold et al, 2018).…”

“…Immature/transitional B cells are less affected compared to memory B cell targeting (Mehta et al, 2019). Although plasmablasts and plasma cells can be affected by dimethyl fumarate therapy (Mehta et al, 2019), immunoglobulin levels are not unduly reduced (Diebold et al, 2018). Importantly, vaccine responses in people on dimethyl fumarate were no different to those treated with beta interferons (von Hehm et al, 2017).…”