PML during dimethyl fumarate treatment of multiple sclerosis: How does lymphopenia matter?

Lehmann‐Horn, Klaus; Penkert, Horst; Grein, Peter; Leppmeier, Ulrich; Teuber‐Hanselmann, Sarah; Hemmer, Bernhard; Berthele, Achim

doi:10.1212/wnl.0000000000002900

Cited by 49 publications

(35 citation statements)

References 4 publications

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“…The relevance of understanding mechanisms underlying DMF-induced lymphopenia is underscored by recent reports of PML developing as a rare complication of DMF treatment in patients with MS. 17,18 Such occurrences of DMF-associated PML in both patients with MS and psoriasis have been associated with severe lymphopenia, typically defined as TLC <500 cells/mm 3 , which occurs in only ∼5% of treated patients. Although particular mechanisms underlying DMF-induced lymphopenia may be common in all treated patients, additional features likely underlie the particularly severe lymphopenia experienced by a small proportion of patients, which would not be captured in this study and merit further investigation.…”

Section: Discussionmentioning

confidence: 99%

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

Ghadiri

Rezk

Li³

et al. 2017

Neurol Neuroimmunol Neuroinflamm

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Objective:To examine the mechanism underlying the preferential CD8+ vs CD4+ T-cell lymphopenia induced by dimethyl fumarate (DMF) treatment of MS.Methods:Total lymphocyte counts and comprehensive T-cell subset analyses were performed in high-quality samples obtained from patients with MS prior to and serially following DMF treatment initiation. Random coefficient mixed-effects analysis was used to model the trajectory of T-cell subset losses in vivo. Survival and apoptosis of distinct T-cell subsets were assessed following in vitro exposure to DMF.Results:Best-fit modeling indicated that the DMF-induced preferential reductions in CD8+ vs CD4+ T-cell counts nonetheless followed similar depletion kinetics, suggesting a similar rather than distinct mechanism involved in losses of both the CD8+ and CD4+ T cells. In vitro, DMF exposure resulted in dose-dependent reductions in T-cell survival, which were found to reflect apoptotic cell death. This DMF-induced apoptosis was greater for CD8+ vs CD4+, as well as for memory vs naive, and conventional vs regulatory T-cell subsets, a pattern which mirrored preferential T-cell subset losses that we observed during in vivo treatment of patients.Conclusions:Differential apoptosis mediated by DMF may underlie the preferential lymphopenia of distinct T-cell subsets, including CD8+ and memory T-cell subsets, seen in treated patients with MS. This differential susceptibility of distinct T-cell subsets to DMF-induced apoptosis may contribute to both the safety and efficacy profiles of DMF in patients with MS.

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Section: Discussionmentioning

confidence: 99%

“…1,2 Postmarketing studies also reported lymphopenia in up to 50% of patients, noting a preferential reduction of CD8 + vs CD4 + T-cell counts. 14–16 Rare cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients taking DMF 17,18 and have been linked with, but not restricted to, sustained severe lymphopenia. 18,19 …”

mentioning

confidence: 99%

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

Ghadiri

Rezk

Li³

et al. 2017

Neurol Neuroimmunol Neuroinflamm

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“…Determine the continuation or suspension of DMF considering the risk and benefit when the lymphocyte count range is 500–800/mm for >6 months PML As of September 2017, five cases of PML that were treated with DMF have been reported globally . The incidence of PML because of DMF treatment was considered to be <0.19/10 000 using data of >260 000 patients who were treated with DMF as of 30 April 2017, worldwide .…”

Section: Four Questions and Answers For Dmf In The 2017 Supplement Ofmentioning

confidence: 99%

“…As of September 2017, five cases of PML that were treated with DMF have been reported globally. [33][34][35][36][37] The incidence of PML because of DMF treatment was considered to be <0.19/10 000 using data of >260 000 patients who were treated with DMF as of 30 April 2017, worldwide. 38 Based on the case reports of PML, patients were aged >50 years, and the lymphocyte count was <500/mm 3 in four of five patients.…”

Section: Pmlmentioning

confidence: 99%

Japanese guidelines for dimethyl fumarate

Niino

Ohashi

Ochi

et al. 2018

Clinical & Exp Neuroim

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A multicenter, randomized, double‐blind, placebo‐controlled, efficacy and safety study of BG00012 in participants from the Asia–Pacific region and other countries with relapsing–remitting multiple sclerosis (APEX), including Japan, established the efficacy of dimethyl fumarate (DMF) in preventing relapses and disease progression in patients with multiple sclerosis (MS). Consequently, in December 2016, DMF was approved as the second oral disease‐modifying drug for MS in Japan. However, the new Japanese guidelines for MS and neuromyelitis optica published in 2017 did not include DMF. Later, after the committee discussed a guideline for DMF, a supplement of the new guidelines for MS and neuromyelitis optica, which included DMF, was published in June 2018; this supplement comprised the following four clinical questions: (i) is DMF effective in preventing relapses in patients with MS?; (ii) is DMF effective in preventing disease progression in patients with MS?; (iii) how to use DMF?; and (iv) what adverse events does DMF possibly cause? Furthermore, the supplement comprised answers to the questions and comments. Overall, this supplement is anticipated to contribute toward the treatment of Japanese MS patients with DMF.

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“…It induces activation of the transcription factors Nfr2 (decreasing inflammation) and NF-κB (modifying cytokines production), and diminishes neuroinflammation by promoting the cytoprotection of CNS cells against oxidative stress (41). DMF induces a pronounced lymphopenia that has been associated with the occurrence of rare and fatal cases of progressive multifocal leukoencephalopathy (PML) associated with JC virus infection (53,54). DMF reduces the number of lymphocytes with a decrease of B-cells and CD4 + and CD8 + T-cells.…”

Section: Dimethyl Fumaratementioning

confidence: 99%

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

Teniente‐Serra¹,

Ramo‐Tello

Martı́nez-Cáceres

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

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Abstract:Advances in the understanding of pathogenic mechanisms of diseases have led to the defining of new biomarkers for diagnosis, prognosis, and therapy response. In this context, flow cytometry has been positioned as one of the most useful technologies for monitoring immune-mediated diseases, such as multiple sclerosis (MS), allowing a detailed analysis of lymphocyte subpopulations in peripheral blood. The autoimmune inflammatory response in MS results in changes in lymphocyte subpopulations that might be useful as surrogate markers for the evaluation of disease activity, progression, and monitoring of therapy response. This chapter discusses the role of T-lymphocyte and B-lymphocyte subpopulations in MS pathogenesis, the effect of MS treatments on these subsets, and their potential usefulness as biomarkers of treatment response.

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PML during dimethyl fumarate treatment of multiple sclerosis: How does lymphopenia matter?

Cited by 49 publications

References 4 publications

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

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

Japanese guidelines for dimethyl fumarate

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

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