Zorc Robert, Redmond Christopher, Sylvester McKella, Maclean Mary, Yamamoto de Almeida Luciana, Quinn Kaitlin A, Tomelleri Alessandro, Campochiaro Corrado, Dagna Lorenzo, Gutierrez-Rodrigues Fernanda, Wells Kristina V, Rankin Cameron, Hait Sabrina Helmold, Palmer Chloe, Corty Robert, Bick Alexander, Lambert Kathi, Buckner Jane H, O'Shea John J, Park Jin Kyun, Gadina Massimo, Grayson Peter C
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Ann Rheum Dis. 2025 Aug;84(8):1401-1411. doi: 10.1016/j.ard.2025.01.049. Epub 2025 Feb 24.
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).
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.
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).
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.
本研究旨在确定白细胞介素6（IL-6）受体中的一种常见单核苷酸多态性（rs2228145，p.Asp358Ala）是否可预测巨细胞动脉炎（GCA）患者对托珠单抗的治疗反应。
对2个独立的GCA患者队列进行rs2228145位点的基因测序。使用流式细胞术评估患者和对照的外周血单个核细胞（PBMC）中白细胞介素6受体（IL-6R）及其共受体gp130的表达。用IL-6刺激相同的PBMC，并评估IL-6的下游靶点：信号转导和转录激活因子3磷酸化（pSTAT3）和IL-17A表达。
总共纳入了100例GCA患者（推导队列n = 58；验证队列n = 42）。rs-2228145变异体在每个队列中均预测了托珠单抗反应。在推导队列中，观察到基因剂量依赖性反应，纯合子患者的反应率为36%，无该变异体的患者反应率为95%（P = 0.003）。在验证队列中，纯合子的托珠单抗反应率为50%，无该变异体的患者反应率为85%（P = 0.04）。GCA患者的CD4 T细胞中，pSTAT3水平在对IL-6刺激的反应中以基因剂量依赖性方式显著升高，而对照组则不然。GCA患者的CD4 T细胞中gp130的膜表达显著高于健康对照，且对IL-6的反应与gp130表达相关。产生IL-17的CD4 T细胞在对IL-6的基因剂量依赖性反应中增加（P < 0.01）。
rs2228145变异体通过增强CD4 T细胞对IL-6的反应，与GCA患者对托珠单抗的治疗反应降低及预后较差相关。
