Evidence map›Paper›PMID 40000263›Full record

ArticleAnnals of the rheumatic diseases2025

A coding single nucleotide polymorphism in the interleukin-6 receptor enhances IL-6 signalling in CD4 T cells and predicts treatment response to tocilizumab in giant cell arteritis.

Robert Zorc, Christopher Redmond, McKella Sylvester, Mary Maclean, Luciana Yamamoto de Almeida, Kaitlin A Quinn, Alessandro Tomelleri, Corrado Campochiaro, Lorenzo Dagna, Fernanda Gutierrez-Rodrigues and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Annals of the rheumatic diseases, 2025. 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
–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

7 citing papers in PubMed.

  1. Review
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  7. HLF transactivatesScience advances · 2025
    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

22 authors.

Robert ZorcNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Christopher RedmondNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
McKella SylvesterNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Mary MacleanNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Luciana Yamamoto de AlmeidaNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Kaitlin A QuinnNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Alessandro TomelleriUnit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Corrado CampochiaroUnit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Lorenzo DagnaUnit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Fernanda Gutierrez-RodriguesNational Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Kristina V WellsNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Cameron RankinNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Sabrina Helmold HaitNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Chloe PalmerNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Robert CortyDepartment of Medicine, Vanderbilt University, Nashville, TN, USA.
Alexander BickDepartment of Medicine, Vanderbilt University, Nashville, TN, USA.
Kathi LambertCenter for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
Jane H BucknerCenter for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
John J O'SheaNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Jin Kyun ParkNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
Massimo GadinaNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Peter C GraysonNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: peter.grayson@nih.gov.

Funding

Vasculitis and Translational MedicineZIAAR041204 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI GRAYSON, PETER · 2015 to 2025
$15.4M
Intramural NIH HHS ZIA AR041204
6 · The paper itself

Abstract

objectivesThe study objective was to determine if a common single nucleotide polymorphism in the interleukin 6 (IL-6) receptor (rs2228145, p.Asp358Ala) predicted treatment response to tocilizumab in giant cell arteritis (GCA).

methodsGenetic sequencing of the rs2228145 locus was performed in 2 independent cohorts of patients with GCA. Peripheral blood mononuclear cells (PBMCs) from patients and controls were evaluated for expression of the interleukin 6 receptor (IL-6R) and its coreceptor, gp130, using flow cytometry. The same PBMCs were stimulated with IL-6 and evaluated for downstream targets of IL-6: STAT3 phosphorylation (pSTAT3) and IL-17A expression.

resultsIn total, 100 patients with GCA were included (derivation cohort n = 58; validation cohort n = 42). The rs2228145 variant predicted tocilizumab response in each cohort. In the derivation cohort, a gene dose-dependent response was observed with a 36% response rate in the homozygous patients and 95% response rate in patients without the variant (P = .003). In the validation cohort, tocilizumab response rates were 50% for homozygotes and 85% for patients without the variant (P = .04). pSTAT3 levels were significantly increased in response to IL-6 stimulation in a gene dose-dependent manner in CD4 T cells from patients with GCA but not controls. CD4 T cells from patients with GCA had significantly higher membrane expression of gp130 than healthy controls, and response to IL-6 correlated with gp130 expression. IL-17 producing CD4 T cells were increased in a gene dose-dependent response to IL-6 (P < .01).

conclusionsThe rs2228145 variant is associated with decreased treatment response to tocilizumab and worse outcomes in GCA by enhancing CD4 T cell response to IL-6.

Indexed as

Antibodies, Monoclonal, HumanizedCD4-Positive T-LymphocytesGiant Cell ArteritisInterleukin-6Receptors, Interleukin-6AgedAged, 80 and overCytokine Receptor gp130FemaleHumansInterleukin-17MaleMiddle AgedPolymorphism, Single NucleotideSignal TransductionSTAT3 Transcription FactorAntibodies, Monoclonal, HumanizedCytokine Receptor gp130IL17A protein, humanIL6R protein, humanInterleukin-17Interleukin-6Receptors, Interleukin-6STAT3 protein, humanSTAT3 Transcription Factortocilizumab

Identifiers

PMID40000263
PMCPMC12313419

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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.