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; Kristina V Wells; Cameron Rankin; Sabrina Helmold Hait; Chloe Palmer; Robert Corty; Alexander Bick; Kathi Lambert; Jane H Buckner; John J O'Shea; Jin Kyun Park; Massimo Gadina; Peter C Grayson

doi:10.1016/j.ard.2025.01.049

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

Ann Rheum Dis. 2025 Feb 24:S0003-4967(25)00203-1. doi: 10.1016/j.ard.2025.01.049. Online ahead of print.

Authors

Robert Zorc¹, Christopher Redmond¹, McKella Sylvester¹, Mary Maclean¹, Luciana Yamamoto de Almeida¹, Kaitlin A Quinn¹, Alessandro Tomelleri², Corrado Campochiaro², Lorenzo Dagna², Fernanda Gutierrez-Rodrigues³, Kristina V Wells¹, Cameron Rankin¹, Sabrina Helmold Hait¹, Chloe Palmer¹, Robert Corty⁴, Alexander Bick⁴, Kathi Lambert⁵, Jane H Buckner⁵, John J O'Shea¹, Jin Kyun Park⁶, Massimo Gadina¹, Peter C Grayson⁷

Affiliations

¹ National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
² Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³ National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Department of Medicine, Vanderbilt University, Nashville, TN, USA.
⁵ Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
⁶ National 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.
⁷ National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: peter.grayson@nih.gov.

PMID: 40000263
DOI: 10.1016/j.ard.2025.01.049

Abstract

Objectives: The 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).

Methods: Genetic 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.

Results: In 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).

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

Published by Elsevier B.V.