Evidence map›Paper›PMID 33468560›Full record

Observational studyNeurology(R) neuroimmunology & neuroinflammation2021

Different Fumaric Acid Esters Elicit Distinct Pharmacologic Responses.

Brian T Wipke, Robert Hoepner, Katrin Strassburger-Krogias, Ankur M Thomas, Davide Gianni, Suzanne Szak, Melanie S Brennan, Maximilian Pistor, Ralf Gold, Andrew Chan and 1 more

Open access · goldAbstract readObservational Study

PubMed Full text at PMC Publisher

In one paragraph

Observational study in Neurology(R) neuroimmunology & neuroinflammation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it

0cells of the map it votes in

7citing papers in PubMed

1.8field-weighted citation impact, top 16% of its field

1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed, 14 citations in OpenAlex.

Mucoadhesive Nanoemulsions for Nose-to-Brain Delivery of Dimethyl Fumarate: Development, Characterization and Proof-of-Concept In Vivo Evaluation.Pharmaceutics · 2026
Article
New onset lymphopenia in patients with relapsing multiple sclerosis switching from long-standing dimethyl fumarate treatment to diroximel fumarate: A case series.Multiple sclerosis (Houndmills, Basingstoke, England) · 2024
Article
Dimethyl Fumarate and Intestine: From Main Suspect to Potential Ally against Gut Disorders.International journal of molecular sciences · 2023
Review
A Narrative Review on Axonal Neuroprotection in Multiple Sclerosis.Neurology and therapy · 2022
Review
Diroximel Fumarate as a Novel Oral Immunomodulating Therapy for Relapsing Forms of Multiple Sclerosis: A Review on the Emerging Data.Drug design, development and therapy · 2022
Review
Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases.International journal of molecular sciences · 2021
Review
A Bibliometric Evaluation of the Top 100 Cited Dimethyl Fumarate Articles.Molecules (Basel, Switzerland) · 2021
Article

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 2 institutions in 1 country.

Brian T WipkeFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Robert HoepnerFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Katrin Strassburger-KrogiasFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Ankur M ThomasFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Davide GianniFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Suzanne SzakFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Melanie S BrennanFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Maximilian PistorFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Ralf GoldFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Andrew ChanFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. Andrew.Chan@insel.ch suzanne.szak@biogen.com.

Robert H ScannevinFrom Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

University of Bern · CHUniversity Hospital of Bern · CH

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

objectiveTo test the hypothesis that dimethyl fumarate (DMF, Tecfidera) elicits different biological changes from DMF combined with monoethyl fumarate (MEF) (Fumaderm, a psoriasis therapy), we investigated DMF and MEF in rodents and cynomolgus monkeys. Possible translatability of findings was explored with lymphocyte counts from a retrospective cohort of patients with MS.

methodsIn rodents, we evaluated pharmacokinetic and pharmacodynamic effects induced by DMF and MEF monotherapies or in combination (DMF/MEF). Clinical implications were investigated in a retrospective, observational analysis of patients with MS treated with DMF/MEF (n = 36).

resultsIn rodents and cynomolgus monkeys, monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited higher brain penetration, whereas MEF was preferentially partitioned into the kidney. In mice, transcriptional profiling for DMF and MEF alone identified both common and distinct pharmacodynamic responses, with almost no overlap between DMF- and MEF-induced differentially expressed gene profiles in immune tissues. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated oxidative stress response pathway was exclusively regulated by DMF, whereas apoptosis pathways were activated by MEF. DMF/MEF treatment demonstrated that DMF and MEF functionally interact to modify DMF- and MEF-specific responses in unpredictable ways. In patients with MS, DMF/MEF treatment led to early and pronounced suppression of lymphocytes, predominantly CD8

conclusionsFumaric acid esters exhibit different biodistribution and may elicit different biological responses; furthermore, pharmacodynamic effects of combinations differ unpredictably from monotherapy. The strong potential to induce lymphopenia in patients with MS may be a result of activation of apoptosis pathways by MEF compared with DMF.

Indexed as

AnimalsCross-Sectional StudiesDimethyl FumarateFemaleFumaratesGene Expression ProfilingHumansImmunosuppressive AgentsMacaca fascicularisMaleMiceMice, Inbred C57BLMultiple SclerosisRatsRats, Sprague-DawleyRetrospective StudiesDimethyl Fumarateethyl fumarateFumaratesImmunosuppressive Agents

Identifiers

PMID33468560

DOI10.1212/NXI.0000000000000950

PMCPMC7862084

OpenAlexW3125798424

What OpenQuestion holds

Textmetadata

LicenceCC BY-NC-ND

Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.