Evidence map›Paper›PMID 40749525›Full record

ArticleEBioMedicine2025

HLA-A∗03:01 as predictive genetic biomarker for glatiramer acetate treatment response in multiple sclerosis: a retrospective cohort analysis.

Brian C Zhang, Tilman Schneider-Hohendorf, Rebecca Elyanow, Beatrice Pignolet, Simon Falk, Christian Wünsch, Marie Deffner, Erik Yusko, Damon May, Daniel Mattox and 46 more

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In one paragraph

Article in EBioMedicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
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

3 citing papers in PubMed.

  1. Review
  2. Big data in multiple sclerosis.Current opinion in neurology · 2026
    Review
  3. 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

56 authors.

Brian C ZhangAdaptive Biotechnologies, Seattle, WA, USA.
Tilman Schneider-HohendorfDepartment of Neurology, University of Muenster, Muenster, Germany.
Rebecca ElyanowAdaptive Biotechnologies, Seattle, WA, USA.
Beatrice PignoletToulouse Institute for Infectious and Inflammatory Diseases (Infinity), University of Toulouse, CNRS, INSERM, UPS, Toulouse, France.
Simon FalkDepartment of Neurology, University of Muenster, Muenster, Germany.
Christian WünschDepartment of Neurology, University of Muenster, Muenster, Germany.
Marie DeffnerDepartment of Neurology, University of Muenster, Muenster, Germany.
Erik YuskoAdaptive Biotechnologies, Seattle, WA, USA.
Damon MayAdaptive Biotechnologies, Seattle, WA, USA.
Daniel MattoxAdaptive Biotechnologies, Seattle, WA, USA.
Eva DawinDepartment of Neurology, University of Muenster, Muenster, Germany.
Lisa Ann GerdesInstitute of Clinical Neuroimmunology, University Hospital, Ludwig Maximilian University Munich, Munich, Germany; Biomedical Center, Faculty of Medicine, Ludwig Maximilian University Munich, Martinsried, Germany; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
Florence BucciarelliToulouse Institute for Infectious and Inflammatory Diseases (Infinity), University of Toulouse, CNRS, INSERM, UPS, Toulouse, France.
Lisa RevieDepartment of Neurology, University of Muenster, Muenster, Germany.
Gisela AntonyCentral Information Office German Competence Network of Multiple Sclerosis, Philipps University Marburg, Marburg, Germany.
Sven JariusDepartment of Neurology, University of Heidelberg, Heidelberg, Germany.
Christiane SeidelDepartment of Neurology, University of Leipzig, Leipzig, Germany.
Makbule SenelDepartment of Neurology, University of Ulm, Ulm, Germany.
Stefan BittnerDepartment of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Felix LuessiDepartment of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Joachim HavlaInstitute of Clinical Neuroimmunology, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
Matthias KnopMax Planck Institute of Psychiatry, Munich, Germany.
Manuel A FrieseInstitute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Susanne RothacherDepartment of Neurology and Clinical Neurophysiology, Medical Faculty, University of Augsburg, Augsburg, Germany.
Anke SalmenDepartment of Neurology, St. Josef-hospital, Ruhr-University Bochum, Bochum, Germany.
Fumie HayashiWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Roland HenryWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Stacy CaillierWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Adam SantanielloWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
University of California San Francisco MS-EPIC TeamWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
German Competence Network Multiple Sclerosis (KKNMS)
Maria SeipeltDepartment of Neurology, University Hospital Marburg, Philipps-University Marburg, Marburg, Germany.
Christoph HeesenInstitute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Sandra NischwitzMax Planck Institute of Psychiatry, Munich, Germany.
Antonios BayasDepartment of Neurology and Clinical Neurophysiology, Medical Faculty, University of Augsburg, Augsburg, Germany.
Hayrettin TumaniDepartment of Neurology, University of Ulm, Ulm, Germany.
Florian Then BerghDepartment of Neurology, University of Leipzig, Leipzig, Germany.
Gerd Meyer Zu HörsteDepartment of Neurology, University of Muenster, Muenster, Germany.
Tania KümpfelInstitute of Clinical Neuroimmunology, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
Catharina C GrossDepartment of Neurology, University of Muenster, Muenster, Germany.
Brigitte WildemannDepartment of Neurology, University of Heidelberg, Heidelberg, Germany.
Martin KerschensteinerInstitute of Clinical Neuroimmunology, University Hospital, Ludwig Maximilian University Munich, Munich, Germany; Biomedical Center, Faculty of Medicine, Ludwig Maximilian University Munich, Martinsried, Germany; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
Ralf GoldDepartment of Neurology, St. Josef-hospital, Ruhr-University Bochum, Bochum, Germany.
Sven G MeuthDepartment of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Frauke ZippDepartment of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Bruce A C CreeWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Jorge OksenbergWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Michael R WilsonWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Stephen L HauserWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Scott S ZamvilWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Luisa KlotzDepartment of Neurology, University of Muenster, Muenster, Germany.
Roland LiblauToulouse Institute for Infectious and Inflammatory Diseases (Infinity), University of Toulouse, CNRS, INSERM, UPS, Toulouse, France.
Harlan RobinsAdaptive Biotechnologies, Seattle, WA, USA.
Joseph J SabatinoWell Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Heinz WiendlDepartment of Neurology, University of Muenster, Muenster, Germany; Department of Neurology and Neurophysiology, University of Freiburg, Freiburg, Germany.
Nicholas SchwabDepartment of Neurology, University of Muenster, Muenster, Germany. Electronic address: Nicholas.Schwab@ukmuenster.de.

Funding

Extension of Combination Therapy for Multiple Sclerosis (eCombiRx)U01NS045719 · NINDS · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI LUBLIN, FRED D · 2003 to 2012
$44.7M
The Role of B cells in the Origin and Progression of Multiple SclerosisR35NS111644 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI STEPHEN L HAUSER · 2019 to 2026
$9.1M
Disease relevance of CD20 expression on T cells in multiple sclerosis patientsR01NS092835 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HAUSER, STEPHEN L · 2015 to 2018
$1.7M
Detection of disease-relevant CD8+ T cells in Multiple SclerosisK08NS107619 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SABATINO, JOSEPH JOHN · 2019 to 2023
$1.0M
NINDS NIH HHS K08 NS107619NINDS NIH HHS R01 NS092835NINDS NIH HHS R35 NS111644NINDS NIH HHS U01 NS045719
6 · The paper itself

Abstract

backgroundGlatiramer acetate (GA) is a well-tolerated treatment for multiple sclerosis (MS) and comparable in its efficacy to high-dose interferon beta (IFN). As a lack of validated treatment response biomarkers for MS hampers progress in personalised treatment, the study goal was to search for biomarkers of a successful treatment response utilising the known observation of T-cell expansions after GA treatment.

methodsT-cell receptor beta chain (TRB) sequencing was performed in 3021 patients with MS: a discovery cohort of 1627 patients with MS, 204 of whom had previously been treated with GA, and then validated in 1394 patients with MS, 424 of whom had previously been treated with GA. Clinical data from 1987 patients with MS treated with GA or IFN and available HLA information from the NationMS, ACP, EPIC, BIONAT, and CombiRx trial cohorts were used for a subsequent analysis.

findingsCommon GA-associated TRB expansions were exclusively detected in HLA-A∗03:01 or in HLA-DRB1∗15:01 backgrounds, within CD8+ effector- or CD4+ central-memory T cells. Both sets of common sequences clonally expanded after GA treatment in a first validation cohort and predicted GA exposure in two further validation cohorts. To evaluate whether restriction of public TRBs to only two HLA alleles is also associated with GA's clinical efficacy, we analysed five cohorts of patients with MS for a potential benefit of the two HLAs concerning the GA response compared to IFN. We consistently found positive interactions with HLA-A∗03:01. This included a relative reduction in relapse risk compared to IFN in HLA-A∗03:01 carriers of 33% (CombiRx: GA + IFN arm: HR 0.67 [95% CI: 0.47-0.96], p = 0.0269) and 34% (CombiRx: GA arm: HR 0.66 [95% CI: 0.45-0.98], p = 0.0377), and in risk to first relapse of 63% (NationMS: HR 0.37 [95% CI: 0.16-0.88], p = 0.0246), but no positive association with DRB1∗15:01.

interpretationHLA-A∗03:01 carrying patients with MS specifically benefit from GA treatment and GA significantly outperforms IFN in these patients. Therefore, determining HLA-A∗03:01 status before choosing a platform treatment for MS, would allow for a personalised treatment decision between GA and IFN.

fundingGerman Research Foundation, National Institutes of Health, National Multiple Sclerosis Society, Valhalla Foundation, Westridge Foundation, Mayer Foundation, German Federal Ministry of Education and Research.

Indexed as

Glatiramer AcetateHLA-A3 AntigenImmunosuppressive AgentsMultiple SclerosisAdultAllelesBiomarkersFemaleGenetic MarkersHumansMaleMiddle AgedReceptors, Antigen, T-Cell, alpha-betaRetrospective StudiesTreatment OutcomeBiomarkersGenetic MarkersGlatiramer AcetateHLA-A3 AntigenImmunosuppressive AgentsReceptors, Antigen, T-Cell, alpha-betaBiomarkerGeneticsGlatiramer acetateHLAMultiple sclerosisTreatment response

Identifiers

PMID40749525
PMCPMC12336691

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