Dimethyl fumarate–induced lymphopenia in MS due to differential T-cell subset apoptosis

Ghadiri, Mahtab; Rezk, Ayman; Li, Rui; Evans, Ashley; Luessi, Felix; Zipp, Frauke; Giacomini, Paul S.; Antel, Jack P.; Bar‐Or, Amit

doi:10.1212/nxi.0000000000000340

Cited by 71 publications

(78 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…19,60,62,[75][76][77][78] The clinical observation of the preferential reduction of peripheral CD8 + compared with CD4 + T cells was also confirmed in vitro. Ghadiri et al 62 found that DMFinduced apoptotic cell death was approximately twice as marked for CD8 + T cells compared with CD4 + T cells. However, the exact mechanism of this effect in treated psoriasis 24,26,27 and MS patients 58,60-65 remains unknown.…”

Section: Biological Effects Of Faes On Peripheral Blood Lymphocytesmentioning

confidence: 65%

“…For all T-cell subsets examined, most in vivo changes occurred within the first 6 months of FAE 27 or DMF treatment. [60][61][62]65 Primarily based on the recently published case series of 19 patients with FAErelated PML, 29,30 we recommend a safety threshold of 200/lL for a CD4 + T-cell count 26 and 140/lL for a CD8 + T-cell count. This increased vigilance in T-cell monitoring appears to be particularly warranted in older patients, 49 especially those who are older than 40 years of age.…”

Section: Discussionmentioning

confidence: 99%

“…24 This effect on CD8 + T cells was then confirmed by several authors in psoriasis patients treated with FAEs 26,27 and MS patients treated with DMF. 58,[60][61][62][63][64][65] FAEs affect CD8 + more than CD4 + T cells, which is important because CD8 + , more than CD4 + T cells, are crucial in the disease containment and clinical outcome of PML and other viral infections. 29,30,39,58,66,67 CD8 + T cells participate in antiviral immunity by recognizing and destroying virus-infected cells through production of toxic chemokines, thereby preventing further spread of the infection.…”

Section: Biological Effects Of Faes On Peripheral Blood Lymphocytesmentioning

confidence: 99%

“…It may be possible that MMF directly induces apoptosis in peripheral blood T cells, although CD4 + or CD8 + T-cell culture experiments showed that MMF does not increase the frequency of apoptotic cells. 62,75 Instead, in vitro DMF leads to the inhibition of T-cell cytokine secretion, T-cell proliferation and, in higher concentrations, the induction of apoptosis in a subpopulation of activated, but not resting, human T cells by impairing the nuclear factor-kappa B signalling pathway in particular. 19,60,62,[75][76][77][78] The clinical observation of the preferential reduction of peripheral CD8 + compared with CD4 + T cells was also confirmed in vitro.…”

Section: Biological Effects Of Faes On Peripheral Blood Lymphocytesmentioning

confidence: 99%

“…15,39 Additional work showed that DMF-induced apoptosis also disproportionately affects circulating memory CD4 + and CD8 + T-cell subsets compared with na€ ıve CD4 + and CD8 + T-cell subsets, independent of the ALC. 60,[62][63][64] New insights into B-and T-cell metabolism suggest that aerobic glycolysis is a hallmark of activated cells, while na€ ıve and memory cells favour oxidative phosphorylation and consume fatty acids. 79,80 Both DMF and MMF target and inactivate the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH).…”

Section: Biological Effects Of Faes On Peripheral Blood Lymphocytesmentioning

confidence: 99%

See 4 more Smart Citations

Fumaric acid ester‐induced T‐cell lymphopenia in the real‐life treatment of psoriasis

Brückner

Höxtermann

Dickel³

et al. 2019

Acad Dermatol Venereol

View full text Add to dashboard Cite

Background Fumaric acid esters ( FAE s) are used to treat psoriasis and are known to cause lymphopenia in roughly 60% of the patients. Much remains to be elucidated about the biological effects of FAE s on lymphocytes. Objective To evaluate the influence of long‐term FAE (Fumaderm ® ) treatment on peripheral blood CD 4 + and CD 8 + T cells, CD 19 + B cells and CD 56 + natural killer ( NK ) cells in psoriasis. Methods In this single‐centre retrospective observational subcohort study, we obtained leucocyte and lymphocyte subset counts before initiating FAE therapy in 371 psoriasis patients (mean age, 47.8 years; 63.3% males) and monitored them during treatment (mean treatment duration, 2.9 years). Multiparametric flow cytometry was used for immunophenotyping. Results FAE s significantly reduced the numbers of CD 4 + T, CD 8 + T, CD 19 + B and CD 56 + NK cells. Among lymphocyte subsets, the mean percentage reduction from baseline was always highest for CD 8 + T cells, with a peak of 55.7% after 2 years of therapy. The risk of T‐cell lymphopenia increased significantly with the age of the psoriasis patients at the time that FAE therapy was initiated. It was significantly decreased for the combination therapy with methotrexate and folic acid (vitamin B9) supplementation. Supporting evidence was found suggesting that T‐cell lymphopenia enhances the effectiveness of FAE therapy. Conclusions Monitoring distinct T‐cell subsets rather than just absolute lymphocyte counts may provide more meaningful insights into both the FAE treatment safety and efficacy. We therefore suggest optimizing pharmacovigilance by additionally monitoring CD 4 + and CD 8 + T‐cell counts at regular intervals, especially in patients of middle to older age. Thus, further prospective studies are needed to establish evidence‐based recommendations to guide dermatologists in the management of psoriasis patients who are taking FAE s and who develop low absolute T‐cell counts.

show abstract

Section: Biological Effects Of Faes On Peripheral Blood Lymphocytesmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Biological Effects Of Faes On Peripheral Blood Lymphocytesmentioning

confidence: 99%

Section: Biological Effects Of Faes On Peripheral Blood Lymphocytesmentioning

confidence: 99%

Section: Biological Effects Of Faes On Peripheral Blood Lymphocytesmentioning

confidence: 99%

See 3 more Smart Citations

Fumaric acid ester‐induced T‐cell lymphopenia in the real‐life treatment of psoriasis

Brückner

Höxtermann

Dickel³

et al. 2019

Acad Dermatol Venereol

View full text Add to dashboard Cite

show abstract

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Maragakis,

de Carvalho,

Weiss

2023

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Numerous potential amyotrophic lateral sclerosis (ALS)‐relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS‐relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well‐established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.

show abstract

Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

Hosseini

Masjedi

Baradaran

et al. 2018

Journal Cellular Physiology

View full text Add to dashboard Cite

Dimethyl fumarate (DMF) is an important oral treatment option for various autoimmune diseases, such as multiple sclerosis (MS) and psoriasis. DMF and its dynamic metabolite, monomethyl fumarate (MMF) are the major compounds that exert therapeutic effects on several pathologic conditions in part, through downregulation of immune responses. The exact mechanism of DMF is yet to be fully understood even though its beneficial effects on the immune system are extensively studied. It has been shown that DMF/MMF can affect various immune cells, which can get involved in both the naive and adaptive immune systems, such as T cells, B cells, dendritic cells, macrophages, neutrophils, and natural killer cells. It is suggested that DMF/MMF may exert their effect on immune cells through inhibition of nuclear factor‐κB translocation, upregulation of nuclear factor erythroid‐derived 2(E2)‐related factor antioxidant pathway, and activation of hydroxyl carboxylic acid receptor 2. In this review, the mechanisms underlying the modulatory functions of DMF or MMF on the main immune cell populations involved in the immunopathogenesis of MS are discussed.

show abstract

Dimethyl fumarate–induced lymphopenia in MS due to differential T-cell subset apoptosis

Cited by 71 publications

References 31 publications

Fumaric acid ester‐induced T‐cell lymphopenia in the real‐life treatment of psoriasis

Fumaric acid ester‐induced T‐cell lymphopenia in the real‐life treatment of psoriasis

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

Contact Info

Product

Resources

About