Characterizing absolute lymphocyte count profiles in dimethyl fumarate–treated patients with MS

Fox, Robert J.; Chan, Andrew; Gold, Ralf; Phillips, J. Theodore; Selmaj, Krzysztof; Chang, Ih; Novas, Mark; Rana, Jitesh; Marantz, Jing L.

doi:10.1212/cpj.0000000000000238

Cited by 102 publications

(128 citation statements)

References 19 publications

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“…Selective depletion of Th1 and Th17 cells would be expected to be protective in MS and could contribute to the therapeutic effect of DMF. Nevertheless, despite the loss of CXCR3 + and CCR6 + cells among lymphopenic patients taking DMF, these patients have not shown a superior clinical response to the drug to date (4, 31)…”

Section: Discussionmentioning

confidence: 99%

Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients

et al. 2015

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Background Dimethyl fumarate (DMF) alters the phenotype of circulating immune cells and causes lymphopenia in a subpopulation of treated MS patients. Objective To phenotypically characterize circulating leukocytes in DMF-treated MS patients. Methods Cross-sectional observational comparisons of peripheral blood from DMF-treated MS patients (n=17 lymphopenic, 24 non-lymphopenic), untreated MS patients (n=17) and healthy controls (n=23) that was immunophenotyped using flow cytometry. Longitudinal samples were analyzed for 13 DMF-treated patients. Results Lymphopenic DMF-treated patients had significantly fewer circulating CD8+ and CD4+ T-cells, CD56dim NK cells, CD19+ B-cells and plasmacytoid dendritic cells compared to controls. CXCR3+ and CCR6+ expression was disproportionately reduced among CD4+ T-cells while the proportion of T regulatory cells was unchanged. DMF did not affect circulating CD56hi NK-cells, monocytes or myeloid dendritic cells. Whether lymphopenic or not, DMF-treated patients had a lower proportion of circulating central and effector memory T cells and concomitant expansion of naïve T cells compared to controls. Conclusions DMF shifts the immunophenotypes of circulating T cells, causing reduction of memory cells and relative expansion of naïve cells regardless of absolute lymphocyte count. This may represent one mechanism of action of the drug. Lymphopenic patients had disproportionate loss of CD8+ T cells, which may affect their immunocompetence.

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Section: Discussionmentioning

confidence: 99%

Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients

et al. 2015

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“…7,8 In a recently published integrated analysis of phase 2b/3/long-term extension studies of DMF in MS (N = 2470), mean absolute lymphocyte counts (ALCs) decreased by approximately 30% during the first year of treatment, then plateaued, remaining higher than the lower limit of normal (0.91 × 10 9 /L) thereafter. 17 Of the 2099 patients treated for at least 6 months, 47 (2.2%) had ALCs less than 0.5 × 10 9 /L persisting for at least 6 months. 17 Mean ALCs remained greater than or equal to the lower limit of normal in 84% and 76% of patients during the first 6 and 12 months, respectively; of these patients, 0.1% and 0% later developed ALCs less than 0.5 × 10 9 /L persisting for at least 6 months.…”

Section: Gi Tolerability Profilementioning

confidence: 95%

“…17 Of the 2099 patients treated for at least 6 months, 47 (2.2%) had ALCs less than 0.5 × 10 9 /L persisting for at least 6 months. 17 Mean ALCs remained greater than or equal to the lower limit of normal in 84% and 76% of patients during the first 6 and 12 months, respectively; of these patients, 0.1% and 0% later developed ALCs less than 0.5 × 10 9 /L persisting for at least 6 months. 17 In the ENDORSE ongoing safety extension study, one case has been reported to date of progressive multifocal leukoencephalopathy (PML), an opportunistic infection, in a patient treated with DMF 240 mg three times daily in the setting of prolonged (≥6 months) severe lymphopenia (approximately <0.5 × 10 9 /L of 3.5 years' duration).…”

Section: Gi Tolerability Profilementioning

confidence: 95%

“…Aside from PML in the setting of prolonged (≥6 months) moderateto-severe lymphopenia, there is no overall increased risk of serious infections, including other opportunistic infections. 15,17 The incidence of alanine aminotransferase elevations of at least 3× the upper limit of normal (ULN) was higher in the DMF versus placebo groups in DEFINE (6% vs. 3%, respectively) but was not observed in CON-enced a GI AE, with a higher incidence of acute lower versus upper GI AEs. Four patients (1.7%) experienced at least one GI-related serious AE, including diarrhea, abdominal pain upper, abdominal pain lower, nausea, salivary gland calculus, and vomiting.…”

Section: Gi Tolerability Profilementioning

confidence: 99%

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Dimethyl Fumarate

Phillips¹,

Agrella²,

Fox³

2017

International Journal of MS Care

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Background: Delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) is indicated for the treatment of relapsing multiple sclerosis. Flushing and gastrointestinal (GI) adverse events (AEs) are common within the first few months of starting DMF therapy. Although most symptoms are mild or moderate in severity, transient, and infrequently result in treatment discontinuation, they nevertheless present a challenge for patients to adhere to therapy and achieve an optimal treatment response. Methods: This review discusses management strategies for the prophylaxis and treatment of common DMF-associated AEs based on clinical trial evidence and real-world experience in clinical practice settings. Results: Before starting DMF therapy, patients should receive counseling on the importance of treatment adherence and the likely occurrence and severity of flushing and GI AEs (nausea, vomiting, diarrhea, and abdominal pain). Management strategies, such as administering DMF with food, using a slower-dose titration schedule, applying temporary dose reductions, and using symptomatic therapies, provide clinicians with several approaches to address DMF tolerability. In particular, DMF coadministration with certain foods (eg, sausage, peanut butter) may prevent or reduce the severity of GI AEs. Taking aspirin 325 mg/day 30 minutes before administering DMF in the first month of therapy can reduce the incidence and severity of flushing without negatively affecting GI-related events. Conclusions: Through continual patient education and support and management of treatment-related flushing and GI AEs, clinicians can help patients adhere to and persist with DMF therapy, thus maximizing treatment benefit.

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“…In fact, 61% of patients kept over the lower limit of the lymphocyte count (>910/mm 3 ). The incidence of lymphopenia (<500/mm 3 ) was 7% . Moderate‐to‐severe lymphopenia might increase the PML risk, and it is recommended to obtain the complete blood cell count and monitor the lymphocyte count for at least every 3 months during the DMF treatment.…”

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

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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Characterizing absolute lymphocyte count profiles in dimethyl fumarate–treated patients with MS

Cited by 102 publications

References 19 publications

Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients

Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients

Dimethyl Fumarate

Japanese guidelines for dimethyl fumarate

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