B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate

Høglund, Rune Alexander; Polak, Justyna; Vartdal, Frode; Holmøy, Trygve; Lossius, Andreas

doi:10.1016/j.msard.2018.08.032

Cited by 12 publications

(10 citation statements)

References 26 publications

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“…Treatment with dimethyl fumarate has not been associated with lower CSF IgG production. 49 Although loss of CSF OCBs has been described in a cohort of interferon-beta-and glatiramer acetate-treated patients with MS, 50 this has not been observed in controlled studies.…”

Section: Discussionmentioning

confidence: 99%

Absence of B Cells in Brainstem and White Matter Lesions Associates With Less Severe Disease and Absence of Oligoclonal Bands in MS

Fransen

Jong

Heß

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo determine whether B-cell presence in brainstem and white matter (WM) lesions is associated with poorer pathological and clinical characteristics in advanced MS autopsy cases.MethodsAutopsy tissue of 140 MS and 24 control cases and biopsy tissue of 24 patients with MS were examined for CD20+ B cells and CD138+ plasma cells. The presence of these cells was compared with pathological and clinical characteristics. In corresponding CSF and plasma, immunoglobulin (Ig) G ratio and oligoclonal band (OCB) patterns were determined. In a clinical cohort of 73 patients, the presence of OCBs was determined during follow-up and compared to status at diagnosis.ResultsIn 34% of active and 71% of mixed active/inactive lesions, B cells were absent, which correlated with less pronounced meningeal B-cell infiltration (p < 0.0001). The absence of B cells and plasma cells in brainstem and WM lesions was associated with a longer disease duration (p = 0.001), less frequent secondary progressive MS compared with relapsing and primary progressive MS (p < 0.0001 and p = 0.046, respectively), a lower proportion of mixed active/inactive lesions (p = 0.01), and less often perivascular T-cell clustering (p < 0.0001). Moreover, a lower CSF IgG ratio (p = 0.006) and more frequent absence of OCBs (p < 0.0001) were noted. In a clinical cohort, numbers of patients without OCBs in CSF were increased at follow-up (27.4%).ConclusionsThe absence of B cells is associated with a favorable clinical and pathological profile. This finding may reflect extremes of a continuum of genetic or environmental constitution, but also a regression of WM humoral immunopathology in the natural course of advanced MS.

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Section: Discussionmentioning

confidence: 99%

Absence of B Cells in Brainstem and White Matter Lesions Associates With Less Severe Disease and Absence of Oligoclonal Bands in MS

Fransen

Jong

Heß

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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“…Because clinical data suggest the presence of lymphopenia is not required for MS relapse-reduction efficacy, the level of ALC reduction or prolonged lymphopenia is not likely to be the primary mechanistic driver of DMF; the contributory effects of cumulative subset-specific changes must still be further explored. While some research has been done to propose specific mechanisms responsible for immune cell loss, 7,8,15,24,25 there are likely multiple mechanisms of action for DMF, as well as patient-intrinsic factors, that are currently not well-understood and lead to the heterogeneous effect of DMF on the immune system.…”

Section: Discussionmentioning

confidence: 99%

Effect of dimethyl fumarate on lymphocytes in RRMS

et al. 2019

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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.

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“…The mechanisms of action are not fully known but may include effects on different T cell subsets. 7 The nrf2 antioxidant pathway 8 and membrane-bound hydroxycarboxylic acid receptor 2 on leukocytes 9 may also be implicated. Side-effects may give clues to the underlying effect mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Gut microbiota composition during a 12-week intervention with delayed-release dimethyl fumarate in multiple sclerosis – a pilot trial

Storm-Larsen

Farbu

et al. 2019

Multiple Sclerosis Journal - Experimental, Translational and Cl

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Introduction: Patients with multiple sclerosis may have a distinct gut microbiota profile. Delayedrelease dimethyl fumarate is an orally administered drug for relapsing-remitting multiple sclerosis, which has been associated with gastrointestinal side-effects in some patients. Objectives: The purpose of this study was to determine if dimethyl fumarate alters the abundance and diversity of commensal gut bacteria, and if these changes are associated with gastrointestinal sideeffects. Methods: Thirty-six patients with relapsing-remitting multiple sclerosis received either dimethyl fumarate (n ¼ 27) or an injectable multiple sclerosis disease-modifying therapy (glatiramer acetate or interferons, n ¼ 9) for 12 weeks. Stool samples were collected at baseline, two and 12 weeks. We included 165 healthy individuals as controls. Results: At baseline, 16 microbial genera were altered in multiple sclerosis patients compared with healthy controls. In the dimethyl fumarate-treated patients (n ¼ 21) we observed a trend of reduced Actinobacteria (p ¼ 0.03, Q FDR ¼ 0.24) at two weeks, mainly driven by Bifidobacterium (p ¼ 0.06, Q FDR ¼ 0.69). At 12 weeks, we observed an increased abundance of Firmicutes (p ¼ 0.02, Q FDR ¼ 0.09), mostly driven by Faecalibacterium (p ¼ 0.01, Q FDR ¼ 0.48). Conclusions: This pilot study did not detect a major effect of dimethyl fumarate on the gut microbiota composition, but we observed a trend towards normalization of the low abundance of butyrateproducing Faecalibacterium after 12 weeks treatment. The study was underpowered to link microbiota to gastrointestinal symptoms.

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B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate

Abstract: The results of this exploratory study support a B-cell mediated mechanism of action for DMF in both blood and CSF.

Cited by 12 publications

References 26 publications

Absence of B Cells in Brainstem and White Matter Lesions Associates With Less Severe Disease and Absence of Oligoclonal Bands in MS

Absence of B Cells in Brainstem and White Matter Lesions Associates With Less Severe Disease and Absence of Oligoclonal Bands in MS

Effect of dimethyl fumarate on lymphocytes in RRMS

Gut microbiota composition during a 12-week intervention with delayed-release dimethyl fumarate in multiple sclerosis – a pilot trial

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